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Find video protocols related to scientific articles indexed in Pubmed.
Trantinterol, a novel ?2-adrenoceptor agonist non-competitively inhibits P-glycoprotein function in vitro and in vivo.
Mol. Pharm.
PUBLISHED: 11-13-2014
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P-glycoprotein (P-gp)-mediated drug-drug interactions are important factors causing adverse effects of drugs in clinical use. The aim of this study was to determine whether trantinterol (also known as SPFF), a novel ?2-adrenoceptor agonist, was a P-gp inhibitor or substrate. The results showed that trantinterol was not a substrate of P-gp but increased rhodamine 123 (Rho 123) uptake by MDCK-MDR1 cells and decreased the efflux transport of both Rho 123 and cyclosporine A (CsA) in bi-directional transport studies across MDCK-MDR1 cell monolayers. This suggested that trantinterol was a P-gp inhibitor but not a P-gp substrate. The mechanism of inhibition was investigated in the P-gp-Glo assay system where it was found that trantinterol inhibited P-gp ATPase activity in a dose-dependent manner. A subsequent study using the antibody binding assay with the conformation-sensitive P-gp-specific antibody UIC2 confirmed that trantinterol decreased UIC2 binding at 10 ?M in contrast to the competitive inhibitor, verapamil. This suggested that trantinterol was a non-competitive inhibitor of P-gp. Finally, a pharmacokinetic study in rat showed that trantinterol significantly increased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of digoxin and paclitaxel (PAC), and the Cmax of cyclosporine A (CsA). In summary, trantinterol is a potent non-competitive P-gp inhibitor which may increase the bioavailability of other P-gp substrate drugs co-administered with it.
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Familial Cerebral Cavernous Angiomas: Clinical and Genetic Features in a Chinese Family with a Frame-Shift Mutation in the CCM1 Gene (krit1).
J. Mol. Neurosci.
PUBLISHED: 09-04-2014
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A few cases of cerebral cavernous malformation (CCM) have been reported in Chinese families with different mutations during the past decade. Herein, we report a case of CCM in a proband in a Chinese family, for whom the mutation type of the CCM remains to be identified. The proband of the family presented a range of clinical symptoms and features that included paralysis, aphasia, multiple lesions in the brain, and cutaneous capillary-venous malformations. PCR was performed to amplify all of the coding exons of the three CCM genes (CCM1, CCM2, and CCM3) in the proband and revealed a heterozygous T deletion in exon 15 (c.1542delT) of CCM1 gene. Targeted mutation analysis in family members demonstrated that this mutation segregated with the disease in the family. This is the first report of a heterozygous CCM1 deletion mutation. Our findings provide a new CCM gene mutation profile in a Chinese family which will be of significance in genetic counseling for CCM.
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Responsive delivery of drug cocktail via mesoporous silica nanolamps.
J Colloid Interface Sci
PUBLISHED: 08-02-2014
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After a substantial advancement in single drug nanocarrier, nanomedicine now demands an integration of nanotechnology with combination therapy to achieve synergistic therapeutic effects. In this respect, a smart and multiple drug shuttling nanotheranostic system is developed which transport diverse kinds of anticancer drugs to cancer cells in a controlled and responsive manner respectively. Synthetically, a significantly high dose of hydrophobic camptothecin (CPT) is first loaded into the porous structure of quantum dots (CdS) coupled mesoporous silica nanocomposite. Subsequently, fluorescent doxorubicin (DOX) molecules are exclusively anchored onto the surface of CdS; as a result, the fluorescence of both CdS and DOX is quenched. Upon exposing to mildly acidic conditions, the fluorescence of both species is recovered, such fluorescent "on-off" states provides an added opportunity to real time sense drug release. In-vitro cell experiment reveals an excellent anticancer efficacy of drug cocktail, merely 3 ?g/ml concentration of multiple drugs loaded nanocarrier reduces the cell viability to 30%. Furthermore, confocal imaging indicates a successful release of both therapeutic entities. We visualize that our newly fabricated multifunctional double drug-carrying nanoparticles can be a valuable addition to next generation of materials that simultaneously deliver cocktail of drugs with imaging functionality.
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A least square method based model for identifying protein complexes in protein-protein interaction network.
Biomed Res Int
PUBLISHED: 07-22-2014
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Protein complex formed by a group of physical interacting proteins plays a crucial role in cell activities. Great effort has been made to computationally identify protein complexes from protein-protein interaction (PPI) network. However, the accuracy of the prediction is still far from being satisfactory, because the topological structures of protein complexes in the PPI network are too complicated. This paper proposes a novel optimization framework to detect complexes from PPI network, named PLSMC. The method is on the basis of the fact that if two proteins are in a common complex, they are likely to be interacting. PLSMC employs this relation to determine complexes by a penalized least squares method. PLSMC is applied to several public yeast PPI networks, and compared with several state-of-the-art methods. The results indicate that PLSMC outperforms other methods. In particular, complexes predicted by PLSMC can match known complexes with a higher accuracy than other methods. Furthermore, the predicted complexes have high functional homogeneity.
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Redox-mediated dissolution of paramagnetic nanolids to achieve a smart theranostic system.
Nanoscale
PUBLISHED: 04-04-2014
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Manganese oxide (Mn3O4) nanoparticles have recently emerged as a promising T1 contrast agent. In this study, for the first time, we demonstrated an interaction of Mn3O4 with a biological system, and found redox sensitive behavior of these paramagnetic nanoparticles in intracellular reducing environment. Inspired by these findings, we for the first time used this interaction for some therapeutic advantages and designed a versatile mesoporous silica based nanotheranostic system to realize redox-activated enhanced magnetic resonance imaging and responsive anticancer drug delivery. Contrary to previous reports, we firstly prepared high quality amine terminated hydrophilic Mn3O4 nanolids, without using multistep ligand exchange strategies. The resulting water stable and small-sized Mn3O4 nanolids were subsequently used as nanolids to cap drug loaded nanochannels of a porous carrier. Exposure to highly prevalent intracellular reducing environment resulted in the steady-state dissolution of these nanolids and attained an intelligent drug release. Furthermore, the redox receptive dissolution of paramagnetic Mn3O4 nanolids into Mn(2+) in turn increases the T1 signal to twofold, providing an added opportunity to even track the feedback of therapy. This study, in addition to simultaneously realizing drug delivery and imaging, also provides a new insight into the fate and interaction of manganese oxide nanoparticles with components of biological systems.
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pH Dictates the Release of Hydrophobic Drug Cocktail from Mesoporous Nanoarchitecture.
ACS Appl Mater Interfaces
PUBLISHED: 11-05-2013
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Combination therapy has been a norm in clinical practice to effectively treat cancer. Besides polytherapy, nowadays, smart and nanobased drug carriers are extensively being explored to deliver drugs according to pathophysiological environment of diseases. In this regard, herein we designed intelligent mesoporous architecture, incorporating both combinational therapy with smart nanotechnology, to simultaneously deliver two highly hydrophobic chemotherapeutic drugs in response to extracellular and/or intracellular acidic environ of tumor. Novelty of the system lies in the employment of acid responsive ZnO QDs to clog not only the nanochannels of mesoporous silica, encapsulating one hydrophobic drug, but also exploitation of chelate forming propensity of another hydrophobic drug (curcumin) to load a significant quantity onto the surface of ZnO nanolids. Cell viability results revealed an extraordinarily high cytotoxic efficiency of that lethal drug cocktail even at a concentration as low as 3 ?g/mL nanocarrier. We envision that this sophisticated nanocarrier, which utilizes both interior pore and exterior surface of nanolids for loading different hydrophobic guest molecules and their subsequent acid responsive release, will undoubtedly, illustrates its remarkable potential in targeted chemotherapy.
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Effects of EPHX1, SCN1A and CYP3A4 genetic polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy.
Epilepsy Res.
PUBLISHED: 08-24-2013
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The pharmacokinetics and pharmacodynamics of carbamazepine (CBZ) vary widely among patients with epilepsy. In this study, we sought to investigate the effects of genetic polymorphisms of the microsomal epoxide hydrolase (EPHX1), the sodium channel ? subunit type I (SCN1A) and the cytochrome P450 3A4 (CYP3A4) genes on plasma CBZ concentrations and pharmacoresistance in Chinese patients with epilepsy. The EPHX1 c.337T>C, c.416A>G, SCN1A IVS5-91G>A or CYP3A4*1G polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism approach or direct DNA sequencing in 83 Chinese patients treated with CBZ monotherapy. Patients with the variant EPHX1 c.416A>G genotypes had higher adjusted plasma CBZ concentrations compared to those with the wild type genotype (P<0.05). In contrast, the SCN1A IVS5-91G>A and CYP3A4*1G variant alleles had no significant effects on CBZ maintenance doses or adjusted CBZ concentrations. There were no associations between all the studied genotypes involving EPHX1 c.337T>C, c.416A>G, SCN1A IVS5-91G>A or CYP3A4*1G polymorphisms and pharmacoresistance in this patient cohort. These results suggest that the EPHX1 c.416A>G polymorphism affects CBZ metabolism in Chinese patients with epilepsy. However, whether it contributes to CBZ resistance needs to be further investigated in a larger cohort of patients.
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Expression and purification of recombinant NRL-Hsp90? and Cdc37-CRL proteins for in vitro Hsp90/Cdc37 inhibitors screening.
Protein Expr. Purif.
PUBLISHED: 05-15-2013
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Hsp90 has emerged as a promising target for cancer treatment. Hsp90 interacts with co-chaperone Cdc37 to mediate the conformational maturation of its kinase client proteins. Screening small molecule inhibitors targeting Hsp90/Cdc37 might be a promising strategy for further cancer therapeutic. In order to establish a recombinant protein system, the novel cloning and purification of full-length human Hsp90? and Cdc37 from BL21 (DE3) Escherichia coli is described here. In this work, we cloned and expressed recombinant NRL-Hsp90? and Cdc37-CRL that represent the full-length human Hsp90? and Cdc37 fused with the split Renilla luciferase (RL) protein fragments. We also expressed the full-length RL protein as a control for inhibitors screening. Moreover, we confirmed that the interaction proteins were able to complement split luciferase fragments and show the RL activity when substrate was added. In comparison, two mutations NRL-Hsp90? (Q133A) and Cdc37 (R167A)-CRL retained only 20% of the complemented RL activities. Six small molecule compounds were tested using this recombinant system. Very interestingly, Sulforaphane, Withaferin A, Celastrol and EGCG all decreased the complemented NRL-Hsp90?/Cdc37-CRL activities in the concentration-dependent manner. In addition, neither Sulforaphane nor Withaferin A showed non-specific inhibition on full length RL activity. However, Celastrol and EGCG showed different RL inhibition levels. The other two compounds LBH-589 and 17-AAG showed neither NRL-Hsp90?/Cdc37-CRL nor RL inhibition activities. These results indicate that purified NRL-Hsp90? and Cdc37-CRL appeared as pure, stable and active conformation, and can be used as an in vitro bioluminescence system for Hsp90/Cdc37 inhibitors screening.
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Chidamide, a novel histone deacetylase inhibitor, synergistically enhances gemcitabine cytotoxicity in pancreatic cancer cells.
Biochem. Biophys. Res. Commun.
PUBLISHED: 03-12-2013
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Pancreatic cancer is a lethal human malignancy with an extremely poor prognosis and urgently requires new therapies. Histone deacetylase inhibitors (HDACIs) represent a new class of anticancer agents and have shown promising antitumor activities in preclinical models of pancreatic cancer. In this study, we sought to determine the antitumor effects of a novel HDACI, chidamide (CS055), in pancreatic cancer cells alone or in combination with gemcitabine. Treatments of BxPC-3 or PANC-1 pancreatic cancer cell lines with chidamide resulted in dose- and time-dependent growth arrest, accompanied by induction of p21 expression. When combined in a sequential schedule, chidamide synergistically enhanced gemcitabine-induced cell growth arrest and apoptosis, accompanied by cooperative downregulation of Mcl-1 and loss of mitochondrial membrane potential (??m). Chidamide enhanced gemcitabine-induced DNA double-strand breaks and S phase arrest, and abrogated the G2/M cell cycle checkpoint, potentially through suppression of CHK1 expression. Our results suggest that chidamide has a therapeutic potential for treating pancreatic cancer, especially in combination with gemcitabine.
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The impact of V30A mutation on transthyretin protein structural stability and cytotoxicity against neuroblastoma cells.
Arch. Biochem. Biophys.
PUBLISHED: 03-12-2013
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Single point mutations in the transthyretin (TTR) gene may cause a hereditary neurodegenerative disease termed familial amyloidotic polyneuropathy (FAP) due to accelerated deposition of amyloid fibrils, resulting in peripheral and autonomic nervous system dysfunction. Recently, we found a Chinese FAP family involving a TTR V30A mutation. To understand the pathogenic mechanisms of this V30A TTR, we investigated the effects of this mutation on TTR quaternary and tertiary structural stabilities and cytotoxicities against neuroblastoma cells along with the most common variant V30M TTR and the wild-type (WT) TTR. Our results showed that the V30A mutation impaired the thermodynamic and kinetic stabilities of the TTR protein by increasing the extent and rate of tetramer dissociation and unfolded monomer and amyloid fibril formation, even to a greater extent than the V30M mutation under several experimental conditions. Further, an obviously cytotoxic effect of the V30A TTR on the human neuroblastoma cell line, IMR-32, was observed. The V30A TTR induced apoptosis and autophagy concomitant with the accumulation of reactive oxygen species (ROS) and DNA double-strand breaks, reflected in the induction of phosphor-H2A.X. These results suggest that the V30A mutation in the TTR gene promotes the formation of unfolded monomers and amyloid fibrils, which potentially contribute to the increased neurotoxicity and the pathology associated with this FAP family.
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Synergistic antitumor interactions between gemcitabine and clofarabine in human pancreatic cancer cell lines.
Mol Med Rep
PUBLISHED: 08-30-2011
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Pancreatic cancer is a highly malignant disease, with a 5-year survival rate of less than 4%. Thus, new therapies for this deadly disease are urgently required. In this study, we sought to investigate whether combination treatments with gemcitabine and clofarabine result in synergistic cytotoxic effects against human pancreatic cancer cells. The type and extent of cytotoxic interactions between gemcitabine and clofarabine in three human pancreatic cancer cell lines were determined by MTT assays and standard isobologram analysis. The effects of the two agents on cell cycle distribution and apoptosis were determined by flow cytometry. Clofarabine significantly and synergistically enhanced gemcitabine cytotoxicities in all of the cell lines tested. This was accompanied by a nearly complete S phase arrest and synergistic induction of apoptosis (cooperativity index = 0.67). Combined treatment of gemcitabine and clofarabine resulted in synergistic cytotoxicities in vitro. Our results strongly suggest potential clinical benefits for using this drug combination to treat pancreatic cancer patients.
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pH-Triggered controlled drug release from mesoporous silica nanoparticles via intracelluar dissolution of ZnO nanolids.
J. Am. Chem. Soc.
PUBLISHED: 05-23-2011
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Acid-decomposable, luminescent ZnO quantum dots (QDs) have been employed to seal the nanopores of mesoporous silica nanoparticles (MSNs) in order to inhibit premature drug (doxorubicin) release. After internalization into HeLa cells, the ZnO QD lids are rapidly dissolved in the acidic intracellular compartments, and as a result, the loaded drug is released into the cytosol from the MSNs. The ZnO QDs behave as a dual-purpose entity that not only acts as a lid but also has a synergistic antitumor effect on cancer cells. We anticipate that these nanoparticles may prove to be a significant step toward the development of a pH-sensitive drug delivery system that minimizes drug toxicity.
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Effects of ABCB1 polymorphisms on plasma carbamazepine concentrations and pharmacoresistance in Chinese patients with epilepsy.
Epilepsy Behav
PUBLISHED: 02-06-2011
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P-glycoprotein may play a role in drug resistance in epilepsy by limiting gastrointestinal absorption and brain access of antiepileptic drugs (AEDs). We sought to investigate the effects of ABCB1 polymorphisms on plasma carbamazepine (CBZ) concentrations and pharmacoresistance in Chinese patients with epilepsy. C1236T, G2677T/A, and C3435T polymorphisms of ABCB1 were genotyped by polymerase chain reaction amplification followed by restriction fragment length polymorphism analysis or direct automated DNA sequencing in 84 patients treated with CBZ monotherapy. Patients with 3435-TT (n=15) had lower adjusted CBZ concentrations than those with 3435-CC (n=30) (P=0.026). However there were no associations between all the studied genotypes, haplotypes, or diplotypes involving ABCB1 C1236T, G2677T/A, and C3435T polymorphisms and pharmacoresistance in the patient cohort. Our results suggest that ABCB1 3435-TT is associated with decreased plasma CBZ levels in Chinese patients with epilepsy. However, whether this contributes to CBZ resistance needs to be further investigated in a larger cohort of patients.
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Mechanism of CYP2C9 inhibition by flavones and flavonols.
Drug Metab. Dispos.
PUBLISHED: 06-25-2009
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This article describes an in vitro investigation of the inhibition of cytochrome P450 (P450) 2C9 by a series of flavonoids made up of flavones (flavone, 6-hydroxyflavone, 7-hydroxyflavone, chrysin, baicalein, apigenin, luteolin, scutellarein, and wogonin) and flavonols (galangin, fisetin, kaempferol, morin, and quercetin). With the exception of flavone, all flavonoids were shown to inhibit CYP2C9-mediated diclofenac 4-hydroxylation in the CYP2C9 RECO system, with K(i) value
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Class I and class II histone deacetylases are potential therapeutic targets for treating pancreatic cancer.
PLoS ONE
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Pancreatic cancer is a highly malignant disease with an extremely poor prognosis. Histone deacetylase inhibitors (HDACIs) have shown promising antitumor activities against preclinical models of pancreatic cancer, either alone or in combination with chemotherapeutic agents. In this study, we sought to identify clinically relevant histone deacetylases (HDACs) to guide the selection of HDAC inhibitors (HDACIs) tailored to the treatment of pancreatic cancer.
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Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy.
Drug Metab. Pharmacokinet.
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Valproic acid (VPA) is one of the most commonly prescribed drugs for the treatment of epilepsy. Interindividual variability in VPA dose and plasma concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between plasma concentrations of VPA and single nucleotide polymorphisms (SNPs) involving uridine diphosphate glucuronosyltransferase (UGT) 1A6 (UGT1A6), UGT2B7, and cytochrome P450 2C9 (CYP2C9) genes in Chinese children with epilepsy. UGT1A6, UGT2B7, and CYP2C9 polymorphisms were identified by the polymerase chain reaction-restriction fragment length polymorphism approach or direct automated DNA sequencing in 98 epileptic patients treated with VPA monotherapy. Patients with double heterozygosities at nucleotide positions T19G, A541G and A552C in the UGT1A6 gene, were associated with higher VPA doses compared to those with wild type or single heterozygosity (p = 0.010). Lower adjusted plasma VPA concentrations were also observed in patients with UGT1A6 double heterozygosities than those with single heterozygosity (p = 0.027). There were no differences in VPA dose or adjusted plasma VPA concentrations among the UGT2B7*2 or CYP2C9*3 genotypic groups. These results suggest that UGT1A6 mutations affect VPA metabolism in epileptic children. It needs to be further investigated in a larger cohort of patients.
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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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