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Find video protocols related to scientific articles indexed in Pubmed.
The Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase (PDHK) and Heat Shock Protein 90 (HSP90).
J. Med. Chem.
PUBLISHED: 11-11-2014
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Upregulation of pyruvate dehydrogenase kinase (PDHK) has been observed in a variety of cancers. Inhibition of PDHK offers an attractive opportunity for the development of novel cancer therapies. To obtain novel PDHK inhibitors, we took advantage of the homology of the ATP-binding pocket between HSP90 and PDHK, and utilized 4,5-diarylisoxazole based HSP90 inhibitor for structural design. Our efforts led to the identification of 5k that inhibited PDHK1 with an IC50 value of 17 nM, which however, showed marginal cellular activity. Further structural optimization resulted in compound 11a with improved cellular activity which could effectively modulate the metabolic profile of cancer cells and led to the inhibition of cancer cell proliferation, evidenced by the increased oxidative phosphorylation and decreased glycolysis and associated oxidative stress. Our results suggested 11a as an excellent lead compound and a favorable biological tool to further evaluate the therapeutic potential of PDHK and HSP90 dual inhibitors in the treatment of cancer.
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Mutations in Cyclodextrin Glycosyltransferase from Bacillus circulans Enhance ?-Cyclization Activity and ?-Cyclodextrin Production.
J. Agric. Food Chem.
PUBLISHED: 11-11-2014
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Cyclodextrin glycosyltransferase (EC 2.4.1.19, CGTase) is used to produce cyclodextrins, which are cyclic glucans with many industrial applications. In the present study, the effects of the amino acid residue at position 577, which is located in calcium-binding site III (CaIII), on cyclization activity and cyclodextrin production were investigated by replacing Asp577 in CGTase from Bacillus circulans STB01 with glutamate, arginine, lysine, and histidine. The results showed that mutations D577E and D577R significantly increased the ?-cyclization activity. The D577R mutant, in particular, displayed a 30.7% increase in the ?-cyclization activity when compared to the wild-type CGTase. Furthermore, under conditions resembling industrial production processes, the D577R and D577E mutants displayed 9.1 and 2.0% enhancement in ?-cyclodextrin production, respectively. More importantly, the higher ?-cyclization activities resulted in a significant reduction in the amount of mutant protein required during the process. Thus, the two mutants were much more suitable for the industrial production of ?-cyclodextrin than the wild-type enzyme.
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Kondo Effect Mediated Topological Protection: Co on Sb(111).
ACS Nano
PUBLISHED: 10-29-2014
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We report on a Kondo effect on Co/Sb(111) mediating topological protection of the surface states against local magnetic perturbations. A sharp scanning tunneling spectroscopic peak near the Fermi energy is interpreted as a fingerprint of the Kondo resonance with a high Kondo temperature of about 200 K. Density function theory calculations reveal that the protruding Co adatoms are responsible for the Kondo peak, while the Co atoms underneath present as nonmagnetic impurities. By identifying the quasiparticle interference wavevectors, we demonstrate that only scattering channels related to backscattering confinements are observed for surfaces with and without the Co adsorption. It suggests that the Kondo effect suppresses the backscattering of the topological surface states and may help to expand the functionality of magnetically coupled topological materials for spintronics applications.
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Staphylococcus aureus infection induces protein A-mediated immune evasion in humans.
J. Exp. Med.
PUBLISHED: 10-27-2014
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Staphylococcus aureus bacterial infection commonly results in chronic or recurrent disease, suggesting that humoral memory responses are hampered. Understanding how S. aureus subverts the immune response is critical for the rescue of host natural humoral immunity and vaccine development. S. aureus expresses the virulence factor Protein A (SpA) on all clinical isolates, and SpA has been shown in mice to expand and ablate variable heavy 3 (VH3) idiotype B cells. The effects of SpA during natural infection, however, have not been addressed. Acutely activated B cells, or plasmablasts (PBs), were analyzed to dissect the ongoing immune response to infection through the production of monoclonal antibodies (mAbs). The B cells that were activated by infection had a highly limited response. When screened against multiple S. aureus antigens, only high-affinity binding to SpA was observed. Consistently, PBs underwent affinity maturation, but their B cell receptors demonstrated significant bias toward the VH3 idiotype. These data suggest that the superantigenic activity of SpA leads to immunodominance, limiting host responses to other S. aureus virulence factors that would be necessary for protection and memory formation.
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Resveratrol Suppresses the Inducible Expression of CYP3A4 Through the Pregnane X Receptor.
J. Pharmacol. Sci.
PUBLISHED: 10-25-2014
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The pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is activated by a number of clinically prescribed drugs and herbal extracts. The inducible expression of several important cytochrome P450 (CYP450) enzymes has been shown to be regulated by the activation of PXR in the liver. In the current study, reporter gene-transfected cells were used to identify potential antagonists of PXR. Here, we showed that resveratrol (RES), a natural polyphenolic compound could significantly suppress the rifampicin-induced PXR transactivation of the CYP3A4 promoter. Treatment of hPXR-over-expressed cells with RES reduced the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. Moreover, the induction of mRNA and protein expression of CYP3A11 by pregnenolone 16?-carbonitrile was also significantly reduced when RES was applied in primary cultures of mouse hepatocytes. Taking together, these findings suggest that RES can attenuate the PXR-mediated induction of CYP3A enzyme. Therefore, it would be possible for RES to antagonize the elevation in CYP3A-mediated drug metabolism by identified PXR activators.
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Sensitization of Cervical Carcinoma Cells to Paclitaxel by an IPP5 Active Mutant.
Asian Pac. J. Cancer Prev.
PUBLISHED: 10-24-2014
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Paclitaxel is one of the best anticancer agents that has been isolated from plants, but its major disadvantage is its dose-limiting toxicity. In this study, we obtained evidence that the active mutant IPP5 (8-60hIPP5m), the latest member of the inhibitory molecules for protein phosphatase 1, sensitizes human cervix carcinoma cells HeLa more efficiently to the therapeutic effects of paclitaxel. The combination of 8-60hIPP5m with paclitaxel augmented anticancer effects as compared to paclitaxel alone as evidenced by reduced DNA synthesis and increased cytotoxicity in HeLa cells. Furthermore, our results revealed that 8-60hIPP5m enhances paclitaxel- induced G2/M arrest and apoptosis, and augments paclitaxel-induced activation of caspases and release of cytochrome C. Evaluation of signaling pathways indicated that this synergism was in part related to down- regulation of NF-?B activation and serine/threonine kinase Akt pathways. We noted that 8-60hIPP5m down- regulated the paclitaxel-induced NF-?B activation, I?B? degradation, PI3-K activity and phosphorylation of the serine/threonine kinase Akt, a survival signal which in many instances is regulated by NF-?B. Together, our observations indicate that paclitaxel in combination with 8-60hIPP5m may provide a therapeutic advantage for the treatment of human cervical carcinoma.
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The -765G>C Polymorphism in the Cyclooxygenase-2 Gene and Digestive System Cancer: a Meta-analysis.
Asian Pac. J. Cancer Prev.
PUBLISHED: 10-24-2014
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Published data regarding associations between the -765G>C polymorphism in cyclooxygenase-2 (COX-2) gene and digestive system cancer risk have been inconclusive. The aim of this study was to comprehensively evaluate the genetic risk of the -765G>C polymorphism in the COX-2 gene for digestive system cancer.
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Potential antigenic explanation for atypical H1N1 infections among middle-aged adults during the 2013-2014 influenza season.
Proc. Natl. Acad. Sci. U.S.A.
PUBLISHED: 10-20-2014
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Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013-2014 influenza season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013-2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group.
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Schisandrol B Protects Against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of Liver Regeneration.
Toxicol. Sci.
PUBLISHED: 10-14-2014
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Acetaminophen (APAP) overdose is the most frequent cause of drug-induced acute liver failure. Schisandra sphenanthera is a traditional hepato-protective Chinese medicine and Schisandrol B (SolB) is one of its major active constituents. In this study, the protective effect of SolB against APAP-induced acute hepatotoxicity in mice and the involved mechanisms were investigated. Morphological and biochemical assessments clearly demonstrated a protective effect of SolB against APAP-induced liver injury. SolB pretreatment significantly attenuated the increases in alanine aminotransferase and aspartate aminotransferase activity, and prevented elevated hepatic malondialdehyde formation and the depletion of mitochondrial glutathione (GSH) in a dose-dependent manner. SolB also dramatically altered APAP metabolic activation by inhibiting the activities of CYP2E1 and CYP3A11, which was evidenced by significant inhibition of the formation of the oxidized APAP metabolite NAPQI-GSH. A molecular docking model also predicted that SolB had potential to interact with the CYP2E1 and CYP3A4 active sites. In addition, SolB abrogated APAP-induced activation of p53 and p21, and increased expression of liver regeneration and antiapoptotic-related proteins such as cyclin D1 (CCND1), PCNA, and BCL-2. This study demonstrated that SolB exhibited a significant protective effect toward APAP-induced liver injury, potentially through inhibition of CYP-mediated APAP bioactivation and regulation of the p53, p21, CCND1, PCNA, and BCL-2 to promote liver regeneration.
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Merremins A-G, Resin Glycosides from Merremia hederacea with Multidrug Resistance Reversal Activity.
J. Nat. Prod.
PUBLISHED: 10-13-2014
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Five new pentasaccharide resin glycosides, named merremins A-E (1-5), two new pentasaccharide resin glycoside methyl esters, named merremins F and G (6, 7), and four known resin glycosides, murucoidin IV, murucoidin V, stoloniferin IV, and murucoidin XVII, were obtained from the aerial parts of Merremia hederacea. This is the first report of resin glycosides obtained from M. hederacea. In addition, the new compounds can be divided into three types: those possessing an 18-membered ring (1-4), compound 5 with a 20-membered ring, and those with an acyclic core (6, 7). Furthermore, the different types of resin glycosides were evaluated for their multidrug resistance reversal activities. Compounds 1, 5, 6, and murucoidin V were noncytotoxic and enhanced the cytotoxicity of vinblastine by 2.3-142.5-fold at 25 ?M. Compound 5 and murucoidin V, with 20-membered rings, were more active than compound 1, with an 18-membered ring.
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[Advances in the research of pharmacogenomics of cyclophosphamide].
Yao Xue Xue Bao
PUBLISHED: 09-20-2014
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Cyclophosphamide (CPA) is the most common alkylating antineoplastic agent, as well as a strong immunosuppressant that is frequently applied to autoimmune diseases and organ transplantation. It is metabolized by cytochrome P450 oxidases (CYPs) to its active metabolite which played a critical role in therapy. CPA has serious and even fatal side effects, and its efficacy and adverse reactions are significantly varied among individuals. In this review, the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the disposition of CPA with the efficacy and adverse effects of CPA were summarized, thereby providing fundamental reference for further pharmacogenomic study of CPA.
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Palladium-catalyzed cross-coupling reactions of 4a,8a-azaboranaphthalene.
Org. Lett.
PUBLISHED: 09-16-2014
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A concise and effective three-step synthesis of 4a,8a-azaboranaphthalene (ABN) has been developed in gram scale. Electrophilic aromatic substitution reactions of ABN provide excellent functional-group-tolerant cross-coupling partners in various Pd-catalyzed cross-coupling reactions (e.g., Sonogashira, Suzuki-Miyaura, or Heck reaction). Photophysical, electrochemical, and DFT calculations all suggest a narrowed HOMO-LUMO gap with extended ?-conjugation characters in the cross-coupled molecules. The ABN moiety as a new fluorophore has a distinct and selective fluorescence response toward Zn(II) and Cd(II) ions, demonstrating great potential for the ABN structural motif in fluorescent chemosensors.
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Wuzhi Tablet (Schisandra Sphenanthera Extract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways.
Drug Metab. Dispos.
PUBLISHED: 09-12-2014
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Schisandra sphenanthera is widely used as a tonic and restorative in many countries to enhance the function of liver and other organs. Wuzhi tablet (WZ) is a preparation of an ethanol extract of Schisandra sphenanthera. Our previous study demonstrated that WZ exerted a protective effect toward acetaminophen (APAP)-induced hepatotoxicity. However, the molecular mechanisms of this protection remain unclear. This study aimed to determine what molecular pathways contributed to the hepatoprotective effects of WZ against APAP toxicity. Administration of WZ 3 days before APAP treatment significantly attenuated APAP hepatotoxicity in a dose-dependent manner and reduced APAP-induced JNK activation. Treatment with WZ resulted in potent inhibition of CYP2E1, CYP3A11, and CYP1A2 activities and then caused significant inhibition of the formation of the oxidized APAP metabolite N-acetyl-p-benzoquinone imine-reduced glutathione. The expression of NRF2 was increased after APAP and/or WZ treatment, whereas KEAP1 levels were decreased. The protein expression of NRF2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was significantly increased by WZ treatment. Furthermore, APAP increased the levels of p53 and its downstream gene p21 to trigger cell cycle arrest and apoptosis, whereas WZ pretreatment could inhibit p53/p21 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, PCNA, and ALR to promote hepatocyte proliferation. This study demonstrated that WZ prevented APAP-induced liver injury by inhibition of cytochrome P450-mediated APAP bioactivation, activation of the NRF2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the p53, p21, cyclin D1, CDK4, PCNA, and ALR to facilitate liver regeneration after APAP-induced liver injury.
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An electrochemical impedance sensor based on a small molecule modified Au electrode for the recognition of a trinucleotide repeat.
Analyst
PUBLISHED: 09-04-2014
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A small molecule modified sensor was developed for the detection of XGG trinucleotide repeats (X = C, T) by electrochemical impedance spectroscopy. The sensor (NCD/MPA/Au) was fabricated by immobilizing the nucleic acid recognition molecule (NCD) on the surface of a gold electrode through a condensation reaction between the amino-terminal end of the NCD linker and carboxylic groups in 3-mercaptopropionic acid that were self-assembled on the electrode surface. After the sensor was incubated with trinucleotide repeats, electrochemical impedance spectroscopy was performed using [Fe(CN)6](3-/4-) as redox marker ions. XGG repeats (X = C, T) could be selectively detected based on the differences in charge transfer resistance (?Rct) even in the presence of other trinucleotide repeats. The relationship between ?Rct and lg [concentration of CGG repeats] for the sensor was linear from 1 nM to 1 ?M, enabling the quantification of the number of repeats. The electrochemical impedance sensor provides a simple and rapid method to detect trinucleotide repeats without requiring labelling and immobilizations of DNA, making it promising for the early diagnosis of neurodegenerative diseases; the sensor may be further extended to the detection of other special sequences of DNA.
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Mammalian target of rapamycin signaling is involved in the vasculogenic mimicry of glioma via hypoxia-inducible factor-1?.
Oncol. Rep.
PUBLISHED: 08-29-2014
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The mammalian target of rapamycin (mTOR) is a crucial regulator in malignant gliomas. Vasculogenic mimicry (VM) describes functional channels established by highly malignant tumor cells that is different from endothelium-lined blood vessels. Our previous studies confirmed the existence and clinical significance of VM in medulloblastoma and glioblastoma. In the present study, by immunohistochemical and CD34/PAS histochemical double-staining, 34 cases (26.8%) with VM structures were identified among a total of 127 glioma cases, and these VM structures were associated with mTOR expression in the glioma specimens. In vitro, U87 malignant glioblastoma cells formed tube structures similar to HUVECs on Matrigel in 3D culture, and mTOR-specific inhibitor rapamycin inhibited VM formation in the U87 malignant glioblastoma cells under both normoxia and hypoxia. In addition, rapamycin and mTOR siRNA inhibited molecules in the signaling cascade of VM formation, particularly HIF-1?. Taken together, our results demonstrated that mTOR signaling is involved in VM formation, and may be a potential therapeutic target for gliomas.
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Discovery of potent N-(isoxazol-5-yl)amides as HSP90 inhibitors.
Eur J Med Chem
PUBLISHED: 08-26-2014
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HSP90 is ubiquitously overexpressed in a broad spectrum of human cancers and has been recognized as an attractive target for cancer treatment. Here, we described the fragment screening, synthesis and structure-activity relationship studies of small molecule inhibitors with 4,5-diarylisoxazole scaffold targeting HSP90. Among them, the compound N-(3-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-((4-morpholinopiperidin-1-yl)methyl)phenyl)isoxazol-5-yl)cyclopropanecarboxamide (108) showed high affinity for binding to HSP90 (FP binding assay, IC50 = 0.030 ?M) and inhibited the proliferation of various human cancer cell lines with averaging GI50 about 88 nM. Compound 108 exhibited its functional inhibition of HSP90 by depleting key signaling pathways and concomitantly elevating of HSP70 and HSP27 in U-87MG cells. Further in vivo studies showed that compound 108 strongly suppressed the tumor growth of human glioblastoma xenograft model U-87MG with T/C = 18.35% at 50 mg/kg q3w/2.5w. Moreover, compound 108 also exhibited good pharmacokinetic properties. Together, our study implicates that compound 108 is a promising candidate of HSP90 inhibitor and is currently advanced to preclinical study.
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Rapid production of novel pre-microRNA agent hsa-mir-27b in Escherichia coli using recombinant RNA technology for functional studies in mammalian cells.
Drug Metab. Dispos.
PUBLISHED: 08-26-2014
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Noncoding microRNAs (miRNAs or miRs) have been revealed as critical epigenetic factors in the regulation of various cellular processes, including drug metabolism and disposition. However, research on miRNA functions is limited to the use of synthetic RNA and recombinant DNA agents. Herein, we show that novel pre-miRNA-27b (miR-27b) agents can be biosynthesized in Escherichia coli using recombinant RNA technology, and recombinant transfer RNA (tRNA)/mir-27b chimera was readily purified to a high degree of homogeneity (>95%) using anion-exchange fast protein liquid chromatography. The tRNA-fusion miR-27b was revealed to be processed to mature miRNA miR-27b in human carcinoma LS-180 cells in a dose- and time-dependent manner. Moreover, recombinant tRNA/miR-27b agents were biologically active in reducing the mRNA and protein expression levels of cytochrome P450 3A4 (CYP3A4), which consequently led to lower midazolam 1'-hydroxylase activity. These findings demonstrate that pre-miRNA agents can be produced by recombinant RNA technology for functional studies.
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Role of Nrf2 activation and NF-?B inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice.
Food Chem. Toxicol.
PUBLISHED: 08-22-2014
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Diammonium glycyrrhizinate (DG), an active compound extracted and purified from liquorices root, has been reported to exhibit antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect and underlying mechanisms of DG on the hepatotoxicity induced by valproic acid (VPA). DG at the dose of 60mg/kg was orally administered with VPA (100mg/kg) to mice once daily for 14 consecutive days. DG treatment attenuated VPA-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. DG prevented VPA-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. The effects of VPA and DG on Nrf2 expression in HepG2 cells were in consistent with that of mice. Furthermore, an increase in the nuclear levels of nuclear factor-kappaB (NF-?B) was observed in the livers of VPA-treated mice that coincided with induction of inflammatory cytokines. In contrast, DG inhibited NF-?B translocation and that subsequently decreased inflammatory cytokines. Taken together, these results demonstrate that DG attenuates VPA-induced liver injury through increasing the expression of Nrf2 mediated phase II/antioxidant enzymes and simultaneously decreasing the expression of inflammatory mediators.
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Characterization of Paraquat-Induced miRNA Profiling Response in hNPCs Undergoing Proliferation.
Int J Mol Sci
PUBLISHED: 08-21-2014
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Aberration during the development of the central nervous system (CNS) due to environmental factors underlies a variety of adverse developmental outcomes. Paraquat (PQ) is a widely studied neurotoxicant that perturbs the normal structure/function of adult CNS. Yet, the impacts of PQ exposure on the developing CNS remain unclear. miRNAs represent a class of small non-coding RNA molecules involved in the regulation of neural development. Thus in the present study, we analyzed the impacts of PQ on the miRNome of human neural progenitor cells (hNPCs) during proliferation by using the Exiqon miRCURY™ LNA Array. A total of 66 miRNAs were identified as differentially expressed in proliferating hNPCs upon PQ treatment. miRTarBase prediction identified 1465 mRNAs, including several genes (e.g., nestin, sox1, ngn1) previously proved to be associated with the neural proliferation and differentiation, as target genes of PQ-induced differentially expressed miRNAs. The database for annotation, visualization and integrated discovery (DAVID) bioinformatics analysis showed that target genes were enriched in regulation of cell proliferation and differentiation, cell cycle and apoptosis as well as tumor protein 53 (p53), Wnt, Notch and mitogen-activated protein kinases (MAPK) signaling pathways (p < 0.001). These findings were confirmed by real-time RT-PCR. Based on our results we conclude that PQ-induced impacts on the miRNA profiling of hNPCs undergoing proliferation may underlie the developmental neurotoxicity of PQ.
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Colorizing pure copper surface by ultrafast laser-induced near-subwavelength ripples.
Opt Express
PUBLISHED: 08-05-2014
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We demonstrate that the colorizing effect of angle dependence can be efficiently and conveniently achieved on the rippled surface of pure copper processed by the femtosecond laser with an out-of-focus method, which greatly improves the machining speed. Such a laser-induced colorization can occur in a wide range of laser fluence, which determines the coverage and morphological characteristics of laser-induced ripples and thus can finely tune the colorizing effect. By inspecting the colors and corresponding spectra of treated areas at different angles, the relationship between the diffracted light central wavelength and the laser-induced near-subwavelength grating is analyzed quantitatively based on the fundamental grating equation with the experimental grating parameters. The spectrum analysis indicates that for the laser fluence increasing in a suitable range, the more clarity and regularity of formed ripples should bring out a more prominent grating effect, which becomes further matching of the grating equation in a larger inspecting angle for the elimination of the influence of the diffused reflection light. In short, the study confirms that the colorizing phenomenon mainly ascribes to the grating diffraction effect of the laser-induced periodic surface ripples, which would help to enable the flexible control of the colorizing effect induced by laser processing on pure copper.
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Molecular-Dynamics-Simulation-Driven Design of a Protease-Responsive Probe for In Vivo Tumor Imaging.
Adv. Mater. Weinheim
PUBLISHED: 08-04-2014
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A protease-responsive probe is developed based on a molecular dynamics simulation method for the rational design of the hairpin "turn" structure of peptides. The Förster resonance energy transfer (FRET)-based probe is used for in vivo detection of legumain, a protease overexpressed in inflammation-related carcinogenesis, providing a potential method for early cancer detection and tumor imaging, and helpful information for better understanding legumain's role in tumorigenesis.
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Asymmetric programming: a highly reliable metadata allocation strategy for MLC NAND flash memory-based sensor systems.
Sensors (Basel)
PUBLISHED: 08-04-2014
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While the NAND flash memory is widely used as the storage medium in modern sensor systems, the aggressive shrinking of process geometry and an increase in the number of bits stored in each memory cell will inevitably degrade the reliability of NAND flash memory. In particular, it's critical to enhance metadata reliability, which occupies only a small portion of the storage space, but maintains the critical information of the file system and the address translations of the storage system. Metadata damage will cause the system to crash or a large amount of data to be lost. This paper presents Asymmetric Programming, a highly reliable metadata allocation strategy for MLC NAND flash memory storage systems. Our technique exploits for the first time the property of the multi-page architecture of MLC NAND flash memory to improve the reliability of metadata. The basic idea is to keep metadata in most significant bit (MSB) pages which are more reliable than least significant bit (LSB) pages. Thus, we can achieve relatively low bit error rates for metadata. Based on this idea, we propose two strategies to optimize address mapping and garbage collection. We have implemented Asymmetric Programming on a real hardware platform. The experimental results show that Asymmetric Programming can achieve a reduction in the number of page errors of up to 99.05% with the baseline error correction scheme.
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Association between non-alcoholic fatty liver disease and chronic kidney disease in population with prediabetes or diabetes.
Int Urol Nephrol
PUBLISHED: 07-21-2014
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The relationship between chronic kidney disease (CKD) and non-alcoholic fatty liver disease (NAFLD) in population with diabetes remains controversial. Our current study aimed to explore the association between NAFLD and CKD in population with prediabetes or diabetes.
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Transcriptional regulation of human hydroxysteroid sulfotransferase SULT2A1 by LXR?.
Drug Metab. Dispos.
PUBLISHED: 07-15-2014
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The nuclear receptor liver X receptor (LXR) plays an important role in the metabolism and homeostasis of cholesterol, lipids, bile acids, and steroid hormones. In this study, we uncovered a function of LXR? (NR1H3) in regulating the human hydroxysteroid sulfotransferase SULT2A1, a phase II conjugating enzyme known to sulfonate bile acids, hydroxysteroid dehydroepiandrosterone, and related androgens. We showed that activation of LXR induced the expression of SULT2A1 at mRNA, protein, and enzymatic levels. A combination of promoter reporter gene and chromatin immunoprecipitation assays showed that LXR? transactivated the SULT2A1 gene promoter through its specific binding to the -500- to -258-base pair region of the SULT2A1 gene promoter. LXR small interfering RNA knockdown experiments suggested that LXR?, but not LXR?, played a dominant role in regulating SULT2A1. In primary human hepatocytes, we found a positive correlation between the expression of SULT2A1 and LXR?, which further supported the regulation of SULT2A1 by LXR?. In summary, our results established human SULT2A1 as a novel LXR? target gene. The expression of LXR? is a potential predictor for the expression of SULT2A1 in human liver.
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JG6, a novel marine-derived oligosaccharide, suppresses breast cancer metastasis via binding to cofilin.
Oncotarget
PUBLISHED: 07-09-2014
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Cofilin, an actin-binding protein which disassembles actin filaments, plays an important role in invasion and metastasis. Here, we discover that JG6, an oligomannurarate sulfate, binds to cofilin, suppresses the migration of human breast cancer cells and cancer metastasis in breast cancer xenograft model. Mechanistically, JG6 occupies actin-binding sites of cofilin, thereby disrupting cofilin modulated actin turnover. Our results highlight the significance of cofilin in cancer and suggest JG6, a cofilin inhibitor, to treat metastatic cancer.
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Expression and characterization of protein Latcripin-3, an antioxidant and antitumor molecule from Lentinula edodes C91-3.
Asian Pac. J. Cancer Prev.
PUBLISHED: 07-08-2014
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In this study, an anti-oxidant and anti-tumor protein Latcripin-3 of Lentinula edodes C91-3 was expressed in Escherichia coli. for the first time. According to the cDNA library, the full-length gene of Latcripin-3 was cloned by the methods of 3'-full rapid amplification of cDNA Ends (RACE) and 5'-full RACE. The structural domain gene of Latcripin-3 was inserted into the pET32 a(+). The functional protein of Latcripin-3 was expressed in Rosetta-gami (DE3) E. coli, evaluated by Western blotting and mass spectrometry. DPPH testing showed that the protein Latcripin-3 can scavenge free radicals remarkably well. The activity of functional protein Latcripin-3 on A549 cells was studied with flow cytometry and the MTT method. The MTT assay results showed that there was a decreases in cell viability in a dose-dependent and time-dependent manner in protein Latcripin-3 treated groups. Flow cytometry demonstrated that Latcripin-3 can induce apoptosis and block S phase dramatically in human A549 lung cancer cells as compared to the control group. At the same time, the cell ultrastructure observed by transmission electron microscopy supported the results of flow cytometry. This research offers new insights and advantages for identifying anti-oxidant and anti-tumor proteins.
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Dynamic and coordinated regulation of KEAP1-NRF2-ARE and p53/p21 signaling pathways is associated with acetaminophen injury responsive liver regeneration.
Drug Metab. Dispos.
PUBLISHED: 07-07-2014
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Acetaminophen (APAP) overdose is the leading cause of drug-induced liver injury. Compensatory liver regeneration is crucial for the final outcome of toxicant-induced injury. However, the molecular mechanisms underlying compensatory liver regeneration in mice after APAP-induced liver injury are not completely understood. This study aimed to investigate the role of dynamic and coordinated regulation of Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2)- antioxidant response element (ARE) and p53/p21 pathways in APAP injury-responsive liver regeneration. We found that mice exhibited massive hepatic toxicity during the first 12 hours after 400 mg/kg APAP treatment, but responsive liver recovery occurred beyond 24 hours as demonstrated by histopathological and biochemical assessments. The expression and nuclear accumulation of NRF2 was increased after APAP treatment. The expression of
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[Effects of carbamazepine on plasma concentrations of valproic acid and its toxic metabolite in epileptic patients].
Yao Xue Xue Bao
PUBLISHED: 07-01-2014
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To investigate the effects of carbamazepine (CBZ) on the plasma concentrations of valproic acid (VPA) and its toxic metabolite 2-propyl-4-pentenoic acid (4-ene VPA) in epileptic patients, the plasma concentrations of VPA and 4-ene VPA were determined, and the effect of CBZ on pharmacokinetics of VPA was evaluated. All patients had been divided into two groups (VPA group, n = 87; and VPA+CBZ group, n = 19). As compared to VPA group, the combination of CBZ significantly (P < 0.01) decreased the trough concentration of VPA [VPA group, (69.5 +/- 28.8) microg x mL(-1); VPA+CBZ group, (46.3 +/- 25.6) microg x mL(-1)] and does-adjusted VPA trough concentration [VPA group, (4.89 +/- 2.21) microg x mL(-1) x mg(-1) x kg(-1); VPA+CBZ group, (3.14 +/- 1.74) microg x mL(-1) x mg(-1) x kg(-1)]. However, the addition of CBZ did not influence the concentration of 4-ene VPA. The present study revealed that coadministration of CBZ can reduce VPA plasma concentration and may impact VPA clinical effect, therefore therapeutic drug mornitoring of VPA should be used when combined use of CBZ and VPA.
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Development, validation, and application of a novel 7-day Caco-2 cell culture system.
J Pharmacol Toxicol Methods
PUBLISHED: 06-16-2014
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Monolayers of Caco-2 cells have been widely accepted as one of the well-established in vitro models to predict intestinal drug permeability and absorption in humans. However, the procedure for culturing the traditional 21-day Caco-2 model is labor intensive and time consuming, which limits its wide application in drug development. The objective of the present study was to develop a rapid Caco-2 model with a 7-day cell culture process.
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Effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel in rats.
Biopharm Drug Dispos
PUBLISHED: 06-13-2014
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Erigeron breviscapus (Vant.) Hand-Mazz, a traditional Chinese medicine, is often co-prescribed with clopidogrel for the treatment of ischemic vascular diseases. Scutellarin is the representative bioactive flavonoid isolated from this herb. The aim of this study was to explore the effect of scutellarin on the metabolism and pharmacokinetics of clopidogrel. The in vitro studies using rat liver microsomes showed that scutellarin significantly inhibited the metabolism of clopidogrel. The IC50 value was 2.1?µm. Ten male rats were employed to investigate the effect of scutellarin on the pharmacokinetics of clopidogrel in vivo. After pretreatment with scutellarin, there were significant increases in the AUC0-? (from 0.9?±?0.4 to 1.7?±?0.6?ng/ml?h; p <0.05) and Cmax (from 0.4?±?0.1 to 0.9?±?0.1?ng/ml; p <0.05) of clopidogrel. The pharmacokinetic data for clopidogrel active metabolite showed significant decreases in AUC0-? (18.2?±?5.6 to 11.4?±?3.7?ng/ml?h; p <0.05) and Cmax (from 8.2?±?1.2 to 4.3?±?0.3?ng/ml; p <0.05) after pretreatment with scutellarin. Collectively, the metabolism and pharmacokinetics of clopidogrel were significantly affected by scutellarin. This study indicated that potential herb-drug interaction between scutellarin and clopidogrel should be taken into consideration in clinical use. Copyright © 2014 John Wiley & Sons, Ltd.
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Antiproliferative protein from the culture supernatant of Lentinula edodes C91-3 mycelia.
J. Agric. Food Chem.
PUBLISHED: 05-29-2014
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We purified and isolated a novel protein (LFP(91-3)A2) with antitumor effect from Lentinula edodes C(91-3) liquid mycelial culture supernatant. LFP(91-3)A2 was purified by (NH4)2SO4 precipitation, ion-exchange chromatography (DEAE-cellulose) and gel filtration chromatography (Sephacryl S-200HR). SDS-PAGE and MALDI-TOF/MS analysis Mascot search showed LFP(91-3)A2 is a new protein with apparent molecular weight of 26 kDa. The effect on tumor cell proliferation was assessed by using MTT assay in vitro, and the LFP(91-3)A2 reduced tumor cell growth obviously in a dose dependent manner (5-15 ?g/mL) (p < 0.05), while it exhibited no toxic effect on normal chick embryo fibroblasts. The antiproliferative mechanism of LFP(91-3)A2 was found to be associated with inducing cell apoptosis by flow cytometry analysis and transmission electron microscopy. The LFP(91-3)A2 is a novel protein from Lentinula edodes with tumor-suppressive activity via inducing apoptosis of tumor cells without toxicity on normal cells and may be beneficial to natural products in clinical treatment.
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Expression levels of insulin-like growth factors and receptors in hepatocellular carcinoma: a retrospective study.
World J Surg Oncol
PUBLISHED: 05-26-2014
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The insulin-like growth factor (IGF) pathway is implicated in the pathogenesis of hepatocellular carcinoma (HCC) and may be important in nonalcoholic fatty liver disease (NAFLD). The aim of this study is to determine expression levels of IGFs and receptors in NAFLD-associated HCC.
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Biotransformation and in vitro metabolic profile of bioactive extracts from a traditional Miao-nationality herbal medicine, Polygonum capitatum.
Molecules
PUBLISHED: 05-23-2014
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Polygonum capitatum Buch.-Ham.ex D. Don, a traditional Miao-nationality herbal medicine, has been widely used in the treatment of various urologic disorders. Recent pharmacological studies demonstrated that a pure compound, FR429, isolated from the ethanol extracts of P. capitatum could selectively inhibit the growth of four hepatocellular carcinoma (HCC) cell lines in a dose-dependent manner. Thus, P. capitatum probably exhibits potential antitumor activity. However, there is very little information on the metabolism of substances present in P. capitatum extracts. In this study, gallic acid, quercetrin, ethanol extracts and ethyl acetate fraction of ethnolic extract (EtOAc fraction) of P. capitatum were cultured anaerobically with rat intestinal bacteria. A highly sensitive and selective liquid chromatography electrospray ionization-ion trap-time of fight mass spectrometry (LC/MSn-IT-TOF) technique was employed to identify and characterize the resulting metabolites. A total of 22 metabolites (M1-M22), including tannins, phenolic acids and flavonoids, were detected and characterized. The overall results demonstrated that the intestinal bacteria played an important role in the metabolism of P. capitatum, and the main metabolic pathways were hydrolysis, reduction and oxidation reactions. Our results provided a basis for the estimation of the metabolic transformation of P. capitatum in vivo.
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Photochemical performance of thylakoid membrane in lead-treated Nymphoides peltatum.
Bull Environ Contam Toxicol
PUBLISHED: 05-15-2014
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Photochemical responses in the thylakoid membrane of Nymphoides peltatum to increasing lead (Pb) concentrations were investigated after 5 days of exposure. Pb accumulation increased in a concentration-dependent manner, with a maximum of 118.44 ?g g(-1) at 100 ?M. Nutrients (Zn, Mg, Mo, Ca, Fe and Mn), ATPase activity and pigment generally increased progressively at Pb concentrations of 12.5 and 25 ?M, but then declined at concentrations of 50 and 100 ?M. Moreover, Pb stress induced an increase in chlorophyll (Chl) a/b ratio in a different extent. No outstanding changes were observed in several Chl a fluorescence parameters at low Pb concentrations (12.5 and 25 ?M), while significant changes (p < 0.05) were observed in these parameters at higher concentrations. The alterations of nutrients, ATPase activity and pigment content were associated with disturbances in the thylakoid membrane, indicated by the quenching of Chl a fluorescence. These results were indicative of a disarray in photochemical activities exerted by Pb phytotoxicity.
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Preparation, transportation mechanisms and brain-targeting evaluation in vivo of a chemical delivery system exploiting the blood-cerebrospinal fluid barrier.
J Drug Target
PUBLISHED: 05-09-2014
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In recent years, specific transportation mechanisms on the blood-brain barrier (BBB) are extensively employed for brain-targeted drug delivery via colloidal nanocarriers. However, in this study, we purposed to exploit the sodium-dependent vitamin C transporter 2 (SVCT2)-mediated transportation on the blood-cerebrospinal fluid barrier to enhance central nervous system penetration of the highly hydrophilic ibuprofen (IBU) by synthesizing a SVCT2-targeted chemical delivery system (CDS), ibuprofen-C6-O-ascorbic acid (IAA). The physicochemical parameters of IAA were determined, and the transporter-mediated transportation mechanism of IAA was explored on a BBB monolayer mode. The overall brain targeting effect of IAA was assayed on mice by measuring the biodistribution of IBU after i.v. administration and calculating the pharmacokinetic parameters and targeting indexes. Results showed that lipophilicity and solubility of IAA was conspicuously improved compared with IBU. At the physiological pH, IAA was stable while in brain homogenates it was easily degraded. Transport studies on the BBB monolayer mode revealed that IAA displayed higher transepithelial permeability than IBU via SVCT2. The biodistribution study in vivo demonstrated that the overall targeting efficiency of IAA was 1.77-fold greater than that of the IBU. In conclusion, the synthetic IAA might be a promising brain-targeted CDS for smuggling small-molecule hydrophilic pharmaceuticals into the brain.
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A phase I-II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin-cyclophosphamide in locally advanced breast cancer.
Breast Cancer Res. Treat.
PUBLISHED: 05-08-2014
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Histone deacetylases (HDACs) are a family of enzymes that regulate chromatin remodeling and gene transcription. Vorinostat is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing HDAC6 and Hsp90 client proteins. Fifty-five patients with clinical stage IIA-IIIC breast cancer received 12 weekly doses of paclitaxel (80 mg/m(2)) plus vorinostat (200-300 mg PO BID) on days 1-3 of each paclitaxel dose plus trastuzumab (for Her2/neu positive disease only), followed by doxorubicin/cyclophosphamide (60/600 mg/m(2) every 2 weeks plus pegfilgrastim). The primary study endpoint was pathologic complete response (pCR). pCR occurred in 13 of 24 evaluable patients with Her2-positive disease (54, 95 % confidence intervals [CI] 35-72 %), which met the prespecified study endpoint. pCR occurred in 4 of 15 patients with triple negative disease (27, 95 % CI 11-52 %) and none of 12 patients with ER-positive, Her2/neu negative disease (0, 95 % CI 0-24 %), which did not meet the prespecified endpoint. ER-positive tumors exhibited lower Ki67 and higher Hsp70 expression, and HDAC6, Hsp70, p21, and p27 expression were not predictive of response. Vorinostat increased acetylation of Hsp90 and alpha tubulin, and reduced expression of Hsp90 client proteins and HDAC6 in the primary tumor. Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin-cyclophosphamide is associated with a high pCR rate in locally advanced Her2/neu positive breast cancer. Consistent with cell line and xenograft data, vorinostat increased acetylation of Hsp90 and alpha tubulin, and decreased Hsp90 client protein and HDAC6 expression in human breast cancers in vivo.
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Mechanism of error caused by isotope-labeled internal standard: accurate method for simultaneous measurement of vitamin D and pre-vitamin D by liquid chromatography/tandem mass spectrometry.
Rapid Commun. Mass Spectrom.
PUBLISHED: 05-07-2014
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Bias of up to 25% has been observed for vitamin D3 and D2 samples exposed to heating during sample preparation, even when isotope-labeled internal standards are used. The goals of this study were to identify the mechanism of the positive bias observed in measuring vitamin D3 and D2 by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and determine a way to eliminate the error source.
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Alteration of Gene Expression Profiling Including GPR174 and GNG2 is Associated with Vasovagal Syncope.
Pediatr Cardiol
PUBLISHED: 04-30-2014
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Vasovagal syncope (VVS) causes accidental harm for susceptible patients. However, pathophysiology of this disorder remains largely unknown. In an effort to understanding of molecular mechanism for VVS, genome-wide gene expression profiling analyses were performed on VVS patients at syncope state. A total of 66 Type 1 VVS child patients and the same number healthy controls were enrolled in this study. Peripheral blood RNAs were isolated from all subjects, of which 10 RNA samples were randomly selected from each groups for gene expression profile analysis using Gene ST 1.0 arrays (Affymetrix). The results revealed that 103 genes were differently expressed between the patients and controls. Significantly, two G-proteins related genes, GPR174 and GNG2 that have not been related to VVS were among the differently expressed genes. The microarray results were confirmed by qRT-PCR in all the tested individuals. Ingenuity pathway analysis and gene ontology annotation study showed that the differently expressed genes are associated with stress response and apoptosis, suggesting that the alteration of some gene expression including G-proteins related genes is associated with VVS. This study provides new insight into the molecular mechanism of VVS and would be helpful to further identify new molecular biomarkers for the disease.
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The 765G>C polymorphism in the cyclooxygenase-2 gene and gastric cancer risk: an update by meta-analysis.
Asian Pac. J. Cancer Prev.
PUBLISHED: 04-26-2014
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The 765G>C polymorphism in cyclooxygenase-2 (COX-2) gene has been extensively investigated for association with gastric cancer (GC). However, the results of different studies have been inconsistent. The aim of this study is to comprehensively evaluate the genetic risk of -765G>C polymorphism in the COX-2 gene for GC.
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Is brain damage really involved in the pathogenesis of obstructive sleep apnea?
Neuroreport
PUBLISHED: 04-17-2014
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Obstructive sleep apnea (OSA) syndrome is a surprisingly complex and highly individualized disease, with different factors contributing toward the disease process. Many factors can induce OSA disease, such as hypertrophy uvula, adenoidectomy, tonsil caused by mechanical obstruction of the airway, airway obstruction on obesity cause of decubitus, etc.; in addition, abnormal structure and function of the central nervous system (CNS) is also one of the important factors. This paper examines the relationship of the CNS with the onset of OSA. Evidence has shown that dysfunction of the CNS may be related to the occurrence of OSA. Although modification of the behaviors of the motor neurons may offer a potentially interesting means of controlling the airway, human afferent and motor pathways that regulate eupnea are still poorly understood. Combining some clinical phenomena of patients with cerebral hemorrhage or brain trauma at the temporal lobe, it seems that no close relation with OSA has been observed in clinical work and animal experiments; however, CNS damage at the temporal lobe is involved in the pathogenesis of OSA. This article examines the role of the CNS in the pathogenesis of OSA and its mechanisms. We have summarized previous findings of OSA-related brain damage, which were obtained by brain functional MRI, clinical, and animal experiment data to better understand the roles of the CNS in the pathogenesis of OSA. More specifically, this review summarizes how altered activity of the limbic system and its related structures could be associated with the occurrence of OSA. This conclusion may contribute toward our understanding of nosogenesis and the treatment of OSA.
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Perceptual training continuously refines neuronal population codes in primary visual cortex.
Nat. Neurosci.
PUBLISHED: 04-16-2014
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Perceptual learning substantially improves visual discrimination and detection ability, which has been associated with visual cortical plasticity. However, little is known about the dynamic changes in neuronal response properties over the course of training. Using chronically implanted multielectrode arrays, we were able to capture day-by-day spatiotemporal dynamics of neurons in the primary visual cortex (V1) of monkeys trained to detect camouflaged visual contours. We found progressive strengthening and accelerating in both facilitation of neurons encoding the contour elements and suppression of neurons responding to the background components. The enhancement of this figure-ground contrast in V1 was closely correlated with improved behavioral performance on a daily basis. Decoding accuracy of a simple linear classifier based on V1 population responses also paralleled the animal's behavioral changes. Our results indicate that perceptual learning shapes the V1 population code to allow a more efficient readout of task-relevant information.
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SOMG-833, a novel selective c-MET inhibitor, blocks c-MET-dependent neoplastic effects and exerts antitumor activity.
J. Pharmacol. Exp. Ther.
PUBLISHED: 04-16-2014
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The hepatocyte growth factor/c-MET signaling axis plays an important role in tumor cell proliferation, metastasis, and tumor angiogenesis, and therefore presents as an attractive target for cancer therapy. Notably, most small-molecule c-MET inhibitors currently undergoing clinical trials are multitarget inhibitors with the unwanted inhibition of additional kinases, often accounting for undesirable toxicity. Here, we discovered SOMG-833 [3-(4-methylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7-(trifluoromethyl) quinoline] as a potent and selective small-molecule c-MET inhibitor, with an average IC50 of 0.93 nM against c-MET, over 10,000-fold more potent compared with 19 tyrosine kinases, including c-MET family members and highly homologous kinases. SOMG-833 strongly suppressed c-MET-mediated signaling transduction regardless of mechanistic complexity implicated in c-MET activation, including MET gene amplification, MET gene fusion, and HGF-stimulated c-MET activation. In a panel of 24 human cancer or genetically engineered model cell lines, SOMG-833 potently inhibited c-MET-driven cell proliferation, whereas cancer cells lacking c-MET activation were markedly less sensitive (at least 15-fold) to the treatment. SOMG-833 also suppressed c-MET-mediated migration, invasion, urokinase activity, and invasive growth phenotype. In addition, inhibition of primary human umbilical vascular endothelial cell (HUVEC) proliferation and downregulation of plasma proangiogenic factor interleukin-8 secretion resulted from SOMG-833 treatment, suggesting its significant antiangiogenic properties. Together, these results led to the remarkable antitumor efficacy of SOMG-833 in vivo, as demonstrated in c-MET-dependent NIH-3T3/TPR-MET, U-87MG, and EBC-1 xenograft models. Collectively, our results suggested SOMG-833 as a promising candidate for highly selective c-MET inhibition and a powerful tool to investigate the sole role of MET kinase in cancer.
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Inhibiton of cytochrome P450 isoenzymes and P-gp activity by multiple extracts of Huang-Lian-Jie-Du decoction.
J Ethnopharmacol
PUBLISHED: 04-03-2014
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Huang-Lian-Jie-Du-Decotion (HLJDD), an important traditional Chinese medicine formula, has been used for various diseases in clinical practice, and thus has high potential to induce cytochrome P450 (CYP) isoenzymes / P-glycoprotein (P-gp) mediated herb-drug interactions (HDIs) with other co-administered drugs.
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Germacranes and m-menthane from Illicium lanceolatum.
Molecules
PUBLISHED: 03-15-2014
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Three new germacrane sesquiterpenes and a new m-menthane monoterpene were isolated together with four known compounds from the pericarp of Illicium lanceolatum, an adulterant to star anise (Illicium verum). All compounds were isolated from Illicium plants for the first time. The absolute stereochemistry of all germacranes and m-menthane was established by a combination of NMR and the modified Mosher's ester method. The biological activity was evaluated on SH-SY5Y neuroblastoma cell line. (1S,5R,7R)-1,5-Dihydroxygermacra-4(15),10(14),11(12)-triene (at 62.5 µM) and (1R,5R,7R)-1,5-dihydroxygermacra-4(15),10(14),11(12)-triene (at 15.6 µM) promoted the proliferation of SH-SY5Y by 36.2% and 45.8%, respectively, after 48 h incubation, indicating potential neurotrophic activity.
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SOMCL-863, a novel, selective and orally bioavailable small-molecule c-Met inhibitor, exhibits antitumor activity both in vitro and in vivo.
Cancer Lett.
PUBLISHED: 03-03-2014
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Deregulation of HGF/c-Met signaling and its driven neoplastic phenotype are associated with a variety of human malignancies. We herein reported SOMCL-863 as a novel selective c-Met inhibitor which effectively abrogated c-Met signaling pathways, thereby leading to substantial impairment of c-Met-dependent cell proliferation, migration, invasion, cell scattering and invasive growth. In EBC-1 and NCI-H1993 xenografts, SOMCL-863 exerted significant anti-tumor efficacy through anti-proliferative effects and antiangiogenic mechanisms, including reduction of tumor cell proliferation and reductions of microvessel density and secretion of proangiogenic factor IL-8. Together with the optimal pharmacokinetic properties, SOMCL-863 is a promising candidate worthy for further evaluation as a treatment of c-Met-driven human cancers.
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Mutations enhance ?-cyclodextrin specificity of cyclodextrin glycosyltransferase from Bacillus circulans.
Carbohydr Polym
PUBLISHED: 02-27-2014
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The effects of amino acid residue at position 31 in the neighborhood of calcium binding site I (CaI) on product specificity of cyclodextrin glycosyltransferase (EC 2.4.1.19, CGTase) were investigated by replacing Ala31 in the CGTase from Bacillus circulans STB01 with arginine, proline, threonine, serine and glycine. The results showed that the mutations A31R, A31P, and A31T resulted in the increases in ?-cyclodextrin-forming activity and ?-cyclodextrin production, indicating that these mutations enhanced ?-cyclodextrin specificity of the CGTase. Especially the mutant A31R displayed approximately 26% increase in ?-cyclodextrin production with a concomitant 41% decrease in ?-cyclodextrin production when compared to the wild-type CGTase. Thus, it was much more suitable for the industrial production of ?-cyclodextrin than the wild-type enzyme. The enhanced ?-cyclodextrin specificity of the mutants might be a result of stabilizing CaI, which also suggested that CaI might play an important role in cyclodextrin product specificity of CGTase.
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Bortezomib induces protective autophagy through AMP-activated protein kinase activation in cultured pancreatic and colorectal cancer cells.
Cancer Chemother. Pharmacol.
PUBLISHED: 01-24-2014
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Bortezomib, a selective and potent inhibitor of the proteasome, has demonstrated broad anti-tumor activities in many malignancies. In the current study, we aimed to understand the potential resistance factor of bortezomib in cultured pancreatic and colorectal cancer cells.
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Curcumin inhibits vasculogenic mimicry through the downregulation of erythropoietin-producing hepatocellular carcinoma-A2, phosphoinositide 3-kinase and matrix metalloproteinase-2.
Oncol Lett
PUBLISHED: 01-21-2014
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Glioblastomas (GBMs) are the most common and aggressive malignant primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry (VM) is often detected. VM is the formation of de novo vascular networks by highly invasive tumor cells, instead of endothelial cells. An understanding of the mechanisms of VM formation will contribute to the targeted therapy of GBMs. In the present study, the efficacy of curcumin (CCM) on VM formation and its mechanisms were investigated. It was found that CCM inhibits the VM formation, proliferation, migration and invasion of human glioma U251 cells in a dose-dependent manner. Furthermore, CCM downregulated the protein and mRNA expression of erythropoietin-producing hepatocellular carcinoma-A2, phosphoinositide 3-kinase and matrix metalloproteinase-2, indicating that CCM may function through these factors for the inhibition of VM formation. These data provide novel insights into the use of CCM to antagonize VM, and may contribute to the angiogenesis-targeted therapy of malignant glioma.
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A 12-Words-for-Life-Nurturing Exercise Program as an Alternative Therapy for Cervical Spondylosis: A Randomized Controlled Trial.
Evid Based Complement Alternat Med
PUBLISHED: 01-14-2014
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In this paper, we carried out a randomized controlled clinical trial to explore the effect of 12-words-for-life-nurturing exercise on patients presenting with cervical spondylosis. After exercise intervention, the mean VAS and NDI scores of the patients decreased significantly and the scores of BP, VT, and MH in SF-36 Health Questionnaire were significantly higher. Exercise therapy showed significant effect on relieving pain and improving vitality and mental health. The 12-words-for-life-nurturing exercise may be a potential effective therapy for patients with cervical spondylosis.
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MicroRNA expression profiles associated with acquired gefitinib?resistance in human lung adenocarcinoma cells.
Mol Med Rep
PUBLISHED: 01-06-2014
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The aim of the present study was to establish, characterize and elucidate the potential mechanisms of acquired gefitinb resistance, using the A549 human lung cancer cell line. A gefitinib?resistant A549 sub?clone was established by exposure to escalating gefitinib concentrations over a period of 16?24 months. Half maximal inhibitory concentration (IC50) values were quantified using a real time cytotoxicity assay. The expression profiles of the parent and resistant sub?clone A549 cells were detected using the µParaflo® Microfluidics Biochip microRNA (miRNA) Microarray. The ArrayPro software was used to analyze the differential expression levels of the miRNA, and bioinformatics software was used to predict the potential target genes of the differentially expressed miRNAs. Quantitative polymerase chain reaction (qPCR) was used to confirm the results of the miRNA microarray. A miRNA mimic was transfected into the gefitinib?resistant cells, in order to predict target gene interaction effects, following gefitinib treatment. Protein expression level differences were confirmed by western?blot analysis. Real time cytotoxicity assays revealed a 3?fold increase in the IC50 values of the gefitinib?resistant sub?clones, as compared with the parent cells. There were marked morphological differences between the parent and resistant cells. In the microarray analysis, the gefitinib?resistant sub?clones had 25 upregulated and 18 downregulated miRNAs, as compared with the parent cells. The qPCR revealed that miR?7 was significantly downregulated, which was concordant with the results of the microarray. The results of the present study suggest that miR?7 may significantly improve the sensitivity of cancer cells to gefitinib. The data presented in the present study provides an experimental basis and theory that miRNAs may be involved in acquired gefitinib?resistance of lung adenocarcinoma, and miR?7 may have potential clinical effects in the reversal of drug resistance.
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Restricted VH/VL usage and limited mutations in gluten-specific IgA of coeliac disease lesion plasma cells.
Nat Commun
PUBLISHED: 01-03-2014
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Coeliac disease (CD), an enteropathy caused by cereal gluten ingestion, is characterized by CD4(+) T cells recognizing deamidated gluten and by antibodies reactive to gluten or the self-antigen transglutaminase 2 (TG2). TG2-specific immunoglobulin A (IgA) of plasma cells (PCs) from CD lesions have limited somatic hypermutation (SHM). Here we report that gluten-specific IgA of lesion-resident PCs share this feature. Monoclonal antibodies were expression cloned from single PCs of patients either isolated from cultures with reactivity to complex deamidated gluten antigen or by sorting with gluten peptide tetramers. Typically, the antibodies bind gluten peptides related to T-cell epitopes and many have higher reactivity to deamidated peptides. There is restricted VH and VL combination and usage among the antibodies. Limited SHM suggests that a common factor governs the mutation level in PCs producing TG2- and gluten-specific IgA. The antibodies have potential use for diagnosis of CD and for detection of gluten.
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Two new species of the genus Epuraea Erichson, 1843 from China (Coleoptera, Nitidulidae, Epuraeinae).
Zookeys
PUBLISHED: 01-01-2014
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Two new species belonging to the consobrina-group of the subgenus Micruria Reitter, 1875 (genus Epuraea Erichson, 1843), Epuraea (Micruria) lanuginosasp. n. and Epuraea (Micruria) pulliginissp. n., found in Sichuan Province, China, are described. Pictures and details of structures important for diagnostics of the new species, including external characters and genitalia are given.
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GRP78 inhibits macrophage adhesion via SR-A.
J Biomed Res
PUBLISHED: 01-01-2014
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Class A scavenger receptor (SR-A) plays an important role in macrophage adhesion. However, the underlying mechanism remains unclear. We previously found that 78?kDa glucose-regulated protein (GRP78) inhibited SR-A-mediated ligand internalization into macrophage by binding to SR-A. The aim of the study was to investigate whether GRP78 could regulate SR-A-mediated cell adhesion. We demonstrated that GRP78 bound directly to SR-A by fluorescence resonance energy transfer (FRET) assay. Overexpression of GRP78 inhibited macrophage adhesion via SR-A. These results suggest that GRP78 may act as an inhibitor of macrophage adhesion via SR-A.
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Activation of Nrf2 protects against triptolide-induced hepatotoxicity.
PLoS ONE
PUBLISHED: 01-01-2014
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Triptolide, the major active component of Tripterygium wilfordii Hook f. (TWHF), has a wide range of pharmacological activities. However, the toxicities of triptolide, particularly the hepatotoxicity, limit its clinical application. The hepatotoxicity of triptolide has not been well characterized yet. The aim of this study was to investigate the role of NF-E2-related factor 2 (Nrf2) in triptolide-induced toxicity and whether activation of Nrf2 could protect against triptolide-induced hepatotoxicity. The results showed that triptolide caused oxidative stress and cell damage in HepG2 cells, and these toxic effects could be aggravated by Nrf2 knockdown or be counteracted by overexpression of Nrf2. Treatment with a typical Nrf2 agonist, sulforaphane (SFN), attenuated triptolide-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. Moreover, the hepatoprotective effect of SFN on triptolide-induced liver injury was associated with the activation of Nrf2 and its downstream targets. Collectively, these results indicate that Nrf2 activation protects against triptolide-induced hepatotoxicity.
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O-GlcNAcylation of Cofilin Promotes Breast Cancer Cell Invasion.
J. Biol. Chem.
PUBLISHED: 11-08-2013
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O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNAc transferase (OGT) are linked to the incidence of metastasis in breast cancer patients, but the molecular basis behind this is not fully known. In this study, we have determined that the actin-binding protein cofilin is O-GlcNAcylated by OGT and mainly, if not completely, mediates OGT modulation of cell mobility. O-GlcNAcylation at Ser-108 of cofilin is required for its proper localization in invadopodia at the leading edge of breast cancer cells during three-dimensional cell invasion. Loss of O-GlcNAcylation of cofilin leads to destabilization of invadopodia and impairs cell invasion, although the actin-severing activity or lamellipodial localization is not affected. Our study provides insights into the mechanism of post-translational modification in fine-tuning the regulation of cofilin activity and suggests its important implications in cancer metastasis.
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Effects of Praeruptorin A and Praeruptorin C, a Racemate Isolated from Peucedanum praeruptorum, on MRP2 through the CAR Pathway.
Planta Med.
PUBLISHED: 11-08-2013
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Praeruptorin A and praeruptorin C, racemic to each other, are main bioactive constituents of the species Peucedanum praeruptorum, traditionally used as a Chinese herbal medicine (also known as Bai-Hua Qian Hu). In the present study, the ability of praeruptorins A and C to activate the constitutive androstane receptor and induce human multidrug resistance-associated protein 2 expressions in HepG2 cells was investigated. The changes in mRNA level, protein expression, and transport activity of multidrug resistance-associated protein 2 were determined by quantitative real-time PCR, Western blot, and the CDF uptake assay, respectively. The effects of constitutive androstane receptor knockdown on multidrug resistance-associated protein 2?mRNA and protein expression were also measured by transient transfection of a specific constitutive androstane receptor siRNA. The results showed that praeruptorin A and praeruptorin C significantly induced the multidrug resistance-associated protein 2?mRNA and protein expression, and enhanced the transport activity of multidrug resistance-associated protein 2. A further study showed that mRNA and protein upregulation were attenuated by transient transfection of a specific constitutive androstane receptor siRNA, suggesting that the upregulation of multidrug resistance-associated protein 2 was mediated by the constitutive androstane receptor. Taken together, our findings indicate that praeruptorin A and praeruptorin C can significantly upregulate multidrug resistance-associated protein 2 expression via the constitutive androstane receptor-mediated pathway in vitro, and this should be taken as an herb-drug interaction.
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In Vivo to In Vitro Effects of Six Bioactive Lignans of Wuzhi Tablet (Schisandra Sphenanthera Extract) on the CYP3A/P-glycoprotein-Mediated Absorption and Metabolism of Tacrolimus.
Drug Metab. Dispos.
PUBLISHED: 11-06-2013
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We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.
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Actively transporting virus like analytes with optofluidics for rapid and ultrasensitive biodetection.
Lab Chip
PUBLISHED: 10-31-2013
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Effective analyte delivery is essential to achieve rapid and sensitive biodetection systems. In this article, we present an actively controlled fluidic system integrated with a suspended plasmonic nanohole sensor to achieve superior analyte delivery efficiency and ultrafast sensor response, as compared to conventional fluidic systems. 70 nm sized virus like analyte solution is used to experimentally demonstrate the system performance improvements. Sensor response time is reduced by one order of magnitude as compared to the conventional methods. A seven orders of magnitude dynamic concentration range from 10(3) to 10(9) particles mL(-1) is quantified, corresponding to a concentration window relevant to clinical diagnosis and drug screening. Our non-destructive detection system, by enabling efficient analyte delivery, fast sensing response and minimal sample volume, opens up opportunities for sensitive, rapid and real-time virus detection in infectious disease control and point-of-care applications.
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Small-Molecule Inhibitors of USP1 Target ID1 Degradation in Leukemic Cells.
Mol. Cancer Ther.
PUBLISHED: 10-15-2013
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Inhibitor of DNA binding 1 (ID1) transcription factor is essential for the proliferation and progression of many cancer types, including leukemia. However, the ID1 protein has not yet been therapeutically targeted in leukemia. ID1 is normally polyubiquitinated and degraded by the proteasome. Recently, it has been shown that USP1, a ubiquitin-specific protease, deubiquitinates ID1 and rescues it from proteasome degradation. Inhibition of USP1 therefore offers a new avenue to target ID1 in cancer. Here, using a ubiquitin-rhodamine-based high-throughput screening, we identified small-molecule inhibitors of USP1 and investigated their therapeutic potential for leukemia. These inhibitors blocked the deubiquitinating enzyme activity of USP1 in vitro in a dose-dependent manner with an IC50 in the high nanomolar range. USP1 inhibitors promoted the degradation of ID1 and, concurrently, inhibited the growth of leukemic cell lines in a dose-dependent manner. A known USP1 inhibitor, pimozide, also promoted ID1 degradation and inhibited growth of leukemic cells. In addition, the growth of primary acute myelogenous leukemia (AML) patient-derived leukemic cells was inhibited by a USP1 inhibitor. Collectively, these results indicate that the novel small-molecule inhibitors of USP1 promote ID1 degradation and are cytotoxic to leukemic cells. The identification of USP1 inhibitors therefore opens up a new approach for leukemia therapy. Mol Cancer Ther; 12(12); 2651-62. ©2013 AACR.
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In vitro identification of cytochrome P450 isoforms responsible for the metabolism of 1-hydroxyl-2, 3, 5-trimethoxy-xanthone purified from Halenia elliptica D. Don.
Chem. Biol. Interact.
PUBLISHED: 10-08-2013
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1-hydroxyl-2, 3, 5-trimethoxyxanthone (HM-1) is one of the main constituents extracted from Halenia elliptica D. Don, which is a traditionally used Tibetan medicinal plant. The aim of this study was to illustrate the proposed metabolic pathways of HM-1 and identify which cytochrome P450 (CYP450) isoforms involved in its metabolism by using pooled human liver microsomes (HLMs) and recombinant CYP450 isoforms with selective chemical inhibitors. Metabolites were identified by high performance liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LCMS(n)-ESI-IT-TOF) and nuclear magnetic resonance spectroscopy (hydrogen-1 NMR and carbon-13 NMR). Three metabolites (M1-M3) were identified, which demonstrated that demethylation and hydroxylation were the major Phase I metabolic reactions for HM-1 in HLMs. The structure of another metabolite (M4) was still unclear. The enzymatic kinetics of M1 (Km=23.19±14.20 ?M) and M2 (Km=32.06±17.09 ?M) exhibited substrate inhibition; whereas, the formation of M3 (Km=5.73±0.70 ?M) and M4 (Km=16.43±5.12 ?M) displayed Michaelis-Menten kinetics. The intrinsic clearance (Vmax/Km) of M3 was highest among these metabolites, suggesting that M3 was the major metabolite of HM-1. Moreover, CYP3A4 and CYP2C8 were the primary CYP450 isoform responsible for the metabolism of HM-1. CYP1A2, CYP2A6, CYP2B6, CYP2C9 and CYP2C19 were also involved in HM-1 metabolism, especially in the formation of M3. This study finally provides evidence of substrate inhibition and metabolism-based drug-drug interaction for the medicinal preparations containing HM-1 used in clinic.
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[Study on the characteristics of radiance calibration using nonuniformity extended source].
Guang Pu Xue Yu Guang Pu Fen Xi
PUBLISHED: 09-25-2013
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Integrating sphere and diffuser are always used as extended source, and they have different effects on radiance calibration of imaging spectrometer with parameter difference. In the present paper, a mathematical model based on the theory of radiative transfer and calibration principle is founded to calculate the irradiance and calibration coefficients on CCD, taking relatively poor uniformity lights-board calibration system for example. The effects of the nonuniformity on the calibration was analyzed, which makes up the correlation of calibration coefficient matrix under ideal and unideal situation. The results show that the nonuniformity makes the viewing angle and the position of the point of intersection of the optical axis and the diffuse reflection plate have relatively large effects on calibration, while the observing distances effect is small; under different viewing angles, a deviation value can be found that makes the calibration results closest to the desired results. So, the calibration error can be reduced by choosing appropriate deviation value.
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[Correlation of visual spectral response with aging and its effect on color discrimination].
Guang Pu Xue Yu Guang Pu Fen Xi
PUBLISHED: 09-25-2013
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The variation in normal observers color perception and discrimination will occur with the aging effect. The authors carried out a psychophysical experiment with the method of binocular observational technique. Three observers at the age of 21, 32 and 58 were organized to match the 9 printed color samples on EIZO monitor with the repetition of 7 times. Groups of data for cross-media color matching with different age were established to investigate the response of photoreceptor cells. The results indicated that with the aging effect the chroma of the matched color will decrease obviously and the spectral response of the blue channel will decrease for blue and purple colors. The results validate the prediction of CIEPO06 model to some extent and provide some theoretical basis and experimental supports for the application of color reproduction and the color evaluation of the products related to age.
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Regulation of human pregnane X receptor and its target gene cytochrome P450 3A by praeruptorin A isolated from the herbal medicine Peucedanum praeruptorum.
Planta Med.
PUBLISHED: 09-13-2013
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Qianhu, the dried roots of Peucedanum praeruptorum, is a well-known traditional Chinese medicinal herb which was officially listed in the Chinese Pharmacopoeia. Praeruptorin A is the major active constituent of Qianhu. Our previous studies show that praeruptorin effectively transactivated the protein expression and catalytic activity of cytochrome P450 3A4 via the constitutive androstane receptor-mediated pathway. However, the effect of praeruptorin on the transactivation of cytochrome P450 3A4 through pregnane X receptor pathway is still unclear. To further elucidate the role of the pregnane X receptor pathway in the up-regulation of cytochrome P450 3A4 by praeruptorin, in this study, the effect of praeruptorin on the cytochrome P450 3A4 gene expression was investigated in mouse primary hepatocytes after knockdown of the pregnane X receptor by transient transfection of its siRNA; and the gene expression, protein expression, and catalytic activity of cytochrome P450 3A4 in the LS174T cells with pregnane X receptor overexpression were determined by real-time PCR, Western blot analysis, and LC-MS/MS-based cytochrome P450 3A4 substrate assay, respectively. We found that the level of cytochrome P450 3a11 gene expression in mouse primary hepatocytes was significantly increased by praeruptorin, but such an induction was suppressed after knockdown of pregnane X receptor by its siRNA. Praeruptorin significantly induced cytochrome P450 3A4?mRNA, protein expression, and functional activity through pregnane X receptor-mediated pathway in pregnane X receptor-overexpression LS174T cells; conversely, induction was not found in LS174T cells untransfected with pregnane X receptor plasmids. These findings suggest that praeruptorin can significantly up-regulate cytochrome P450 3A4 gene via the pregnane X receptor-mediated pathway, and this should be taken into consideration in potential herb-drug interactions.
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Mismatch repair protein MSH2 regulates translesion DNA synthesis following exposure of cells to UV radiation.
Nucleic Acids Res.
PUBLISHED: 09-12-2013
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Translesion DNA synthesis (TLS) can use specialized DNA polymerases to insert and/or extend nucleotides across lesions, thereby limiting stalled replication fork collapse and the potential for cell death. Recent studies have shown that monoubiquitinated proliferating cell nuclear antigen (PCNA) plays an important role in recruitment of Y-family TLS polymerases to stalled replication forks after DNA damage treatment. To explore the possible roles of other factors that regulate the ultraviolet (UV)-induced assembly of specialized DNA polymerases at arrested replication forks, we performed immunoprecipitation experiments combined with mass spectrometry and established that DNA polymerase kappa (Pol?) can partner with MSH2, an important mismatch repair protein associated with hereditary non-polyposis colorectal cancer. We found that depletion of MSH2 impairs PCNA monoubiquitination and the formation of foci containing Pol? and other TLS polymerases after UV irradiation of cells. Interestingly, expression of MSH2 in Rad18-deficient cells increased UV-induced Pol? and REV1 focus formation without detectable changes in PCNA monoubiquitination, indicating that MSH2 can regulate post-UV focus formation by specialized DNA polymerases in both PCNA monoubiquitination-dependent and -independent fashions. Moreover, we observed that MSH2 can facilitate TLS across cyclobutane pyrimidine dimers photoproducts in living cells, presenting a novel role of MSH2 in post-UV cellular responses.
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Comparison of aspiration-sclerotherapy versus laparoscopic decortication in management of symptomatic simple renal cysts.
J Xray Sci Technol
PUBLISHED: 09-06-2013
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To perform a retrospective study to compare the efficiency, safety and costs using aspiration-sclerotherapy with 95% ethanol vs. laparoscopic decortications in management of symptomatic simple renal cysts.
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Molecularly targeted cancer therapy: some lessons from the past decade.
Trends Pharmacol. Sci.
PUBLISHED: 08-21-2013
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The tremendous advances achieved in the understanding of cancer biology have delivered unprecedented progress in molecularly targeted cancer therapy in the past decade. The fast growing category of targeted anticancer agents available for clinical use is accompanied by a conceptual revolution in anticancer drug development. Nevertheless, molecularly targeted cancer therapy remains challenged by a high failure rate and an extremely small proportion of patients that can benefit. It is pivotal to take lessons from the past and seek new solutions. This review discusses conceptual progress and remaining challenges in molecularly targeted cancer therapy, and proposes feasible alternatives to increase chances of clinical success in the future.
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[Interference hyperspectral data compression based on spectral classification and local DPCM].
Guang Pu Xue Yu Guang Pu Fen Xi
PUBLISHED: 08-03-2013
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In order to get a high compression ratio, according to the spatial dimension correlation and the interference spectral dimension correlation of interference hyperspectral image data, the present article provides a new compression algorithm that combines spectral classification with local DPCM. This algorithm requires spectral classification for the whole interference hyperspectral image to get a classification number matrix corresponding to the two-dimensional space and a spectral classification library corresponding to the interference spectra first, then local DPCM is performed for the spectral classification library to get a further compression. As the first step of the compression, the spectral classification is very important to the compression effect. This article analyzes the differences of compression effect with different standard and different accuracy of classification, the relative Euclidean distance standard is better than the angle standard and the interference RQE standard. Finally, this article chooses an appropriate standard of compression and achieves the combined compression algorithm with programming. Compared to JPEG2000, the compression effect of combined compression algorithm is better.
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[Induction of UGT1A1 expression by praeruptorin A and praeruptorin C through hCAR pathway].
Yao Xue Xue Bao
PUBLISHED: 07-30-2013
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This study is purposed to investigate the effects of praeruptorin A (PA) and praeruptorin C (PC) on UGT1A1 in HepG2 cells through hCAR pathway. PA and PC were incubated with HepG2 cells for 24 h and 48 h, mRNA and protein expressions of UGT1A1 were determined by real-time PCR and Western blotting assays. Additionally, effects of PA and PC on UGT1A1 mRNA and protein expressions were also measured after transient transfection of a specific CAR siRNA for 72 h in HepG2 cells. UGT1A1 mRNA and protein expression levels were significantly increased by PA and PC after incubation for 48 h. Moreover, the mRNA and protein up-regulations of UGT1A1 were attenuated by transient transfection of a specific CAR siRNA, suggesting the induction was mediated by CAR. The results suggest that PA and PC can significantly up-regulate UGT1A1 expression partially via the CAR-mediated pathway.
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Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models.
Acta Pharmacol. Sin.
PUBLISHED: 07-17-2013
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Aim:To investigate the effects of phorbol 12-myristate 13-acetate (PMA), a PKC activator, on P-glycoprotein-mediated efflux of digoxin in two cell transport models.Methods:Caco-2 cells, wild MDCKII cells (MDCKII-WT) and MDCKII cells transfected stably with human MDR1-gene encoding P-gp (MDCKII-MDR1) were examined. Cell viability was evaluated with MTT assay. Bidirectional transport of digoxin was evaluated in these cells. Intracellular ATP level was measured using ATP assay. P-gp ATPase activity was analyzed using a Pgp-Glo(TM) assay.Results:PMA (10 ?mol/L) did not reduce the viability of the 3 types of cells. In Caco-2 and MDCKII-MDR1 cell monolayers, PMA (1, 10 and 100 nmol/L) dose-dependently inhibited the basolateral to apical transport of digoxin, but did not change the apical to basolateral transport. In addition, PMA did not affect both the basolateral to apical and apical to basolateral transport of digoxin in MDCKII-WT cell monolayer. In agreement with the above results, PMA dose-dependently reduced intracellular ATP level and stimulated P-gp ATPase activity in both Caco-2 and MDCKII-MDR1 cells. Verapamil (a positive control, 100 ?mol/L) caused similar inhibition on digoxin efflux as PMA did, whereas 4?-PMA (a negative control, 100 nmol/L) had no effect.Conclusion:PMA significantly inhibited P-gp-mediated efflux of digoxin in both Caco-2 and MDCKII-MDR1 cell monolayers via PKC activation.
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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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