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1.
Cells Tissues Organs ; : 1-12, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31726456

RESUMO

OBJECTIVE: To elaborate the mechanism of miR-150 in the regulation of the NF-κB signal pathway in intervertebral disc degeneration (IDD) by targeting P2X7. METHODS: The degenerative and normal intervertebral disc tissues were collected to detect the expressions of miR-150 and P2X7. Nucleus pulposus cells were transfected and divided into different groups. Cell apoptosis was determined by flow cytometry and TUNEL staining. The expressions of IL-6, TNF-α, MMP-3, MMP-13, Cox-2, iNOS, collagen II and aggrecan, as well as NF-κB-associated proteins were measured by qRT-PCR and Western blotting. Furthermore, IDD rat models were established to validate the role of miR-150 in vivo. RESULTS: miR-150 was down-regulated but P2X7 was up-regulated in the degenerative intravertebral disc tissues. The apoptosis of nucleus pulposus cells in the IL-1ß-induced group with the transfection of miR-150 mimic and siP2X7 was significantly decreased, with reduced levels of IL-6, TNF-α, MMP-3, MMP-13, Cox-2 and iNOS, increased levels of collagen II and aggrecan, as well as decreased P2X7, p-p65/p65 and cleaved caspase-3. However, the above factors showed an opposite tendency after treatment with miR-150 inhibitor. Furthermore, the P2X7 siRNA transfection could reverse the effects caused by miR-150 inhibitor. Simultaneously, pcDNA P2X7 transfection also inhibited the function of miR-150 mimic in IL-1ß-induced nucleus pulposus cells. In vivoexperiments further verified the protective role of miR-150 in IDD rats. CONCLUSION: miR-150 may alleviate the degeneration of the intervertebral disc partially since it could restrict the NF-κB pathway by targeting P2X7, and thereby inhibiting IL-1ß-induced matrix catabolism, inflammatory responses and apoptosis of the nucleus pulposus cells.

2.
Arch Toxicol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31712840

RESUMO

The main purpose of this study was to verify the hypothesis that cognitive dysfunctions induced by arsenic exposure were related to the changes of D-serine metabolism in the hippocampus of offspring mice. Mother mice and their offsprings were exposed to 0, 15, 30 or 60 mg/L sodium arsenite (NaAsO2) through drinking water from the first day of gestation until the end of lactation. D-serine levels in the hippocampus of mice of postnatal day (PND) 10, 20 and 40 were examined by high-performance liquid chromatography. Expressions of serine racemase (SR), D-amino acid oxidase (DAAO), alanine-serine-cysteine transporter-1 (asc-1) and subunits of N-methyl-D-aspartate receptors (NMDARs) in the hippocampus of mice were measured by Western blot and Real-time RT-PCR. Results showed that arsenic exposure significantly decreased D-serine levels of mice exposed to 60 mg/L NaAsO2. Exposure to 60 mg/L NaAsO2 could inhibit both mRNA and protein expression of SR, whereas increase in the protein expression of DAAO, only enhances the mRNA levels of DAAO of PND 20 mice. In addition, arsenic exposure could upregulate protein expression of asc-1. The mRNA and protein levels of NR1, NR2A and NR2B in the hippocampus of mice were down-regulated by arsenic. Findings from this study suggested that SR might play an important role in the reduction of D-serine levels caused by arsenic exposure, which might further influence the levels of NMDAR subunits especially on PND20, and then might disturb the function of NMDARs and cause the deficits of learning and memory ability of offspring mice.

3.
Sci Total Environ ; 694: 133534, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31756840

RESUMO

China currently faces environmental challenges of lower air quality, partly as a result of industrial activities. The aim of this study was to investigate the role of iron and steelmaking facilities to regional air quality in four selected industry dominated urban centres in China. Nine different particle size ranges present in atmospheric particles collected from four sites in Kunming (KM), Wuhan (WH), Nanjing (NJ) and Ningbo (NB) were analysed and compared with particles collected at one background site at the Ningbo Nottingham University (UN) with very little industrial influence in China. Similar mass concentration levels of particulate matter PM2.1 and PM1.1 were found at the three sites near older iron and steelmaking plants (KM, WH and NJ). Significantly lower levels of PM2.1 and PM1.1 were collected at the fourth site (NB), which is near to a modern and coastal iron and steelmaking plant. The particles collected had the highest mass concentration in the aerodynamic diameter range of 3.3-9.0 µm for all sites, except for the background site (UN). Scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy, and inductively coupled plasma were used to determine the surface morphology and particle chemistry. Al, Ca, Fe, K, Mg, Na and Zn were found as the most abundant elements in all samples. The enrichment factors show that elements As, Cd, Cr, Cu, Pb and Zn were significantly enriched in particles, especially in fine particles, posing an adverse impact on human health. This study can be used to assist the development of particle monitoring programmes in the vicinity of industrial areas and also help to establish an elemental modality dataset on the exposure and risk assessments of atmospheric particles.

4.
Toxicol Appl Pharmacol ; 386: 114826, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31730783

RESUMO

The widespread use and high abuse liability of tobacco products has received considerable public health attention, in particular for youth, who are vulnerable to nicotine addiction. In this study, adult and adolescent squirrel monkeys were used to evaluate age-related metabolism and pharmacokinetics of nicotine after intravenous administration. A physiologically-based pharmacokinetic (PBPK) model was created to characterize the pharmacokinetic behaviors of nicotine and its metabolites, cotinine, trans-3'-hydroxycotinine (3'-OH cotinine), and trans-3'-hydroxycotinine glucuronide (3'-OH cotinine glucuronide) for both adult and adolescent squirrel monkeys. The PBPK nicotine model was first calibrated for adult squirrel monkeys utilizing in vitro nicotine metabolic data, plasma concentration-time profiles and cumulative urinary excretion data for nicotine and metabolites. Further model refinement was conducted when the calibrated adult model was scaled to the adolescents, because adolescents appeared to clear nicotine and cotinine more rapidly relative to adults. More specifically, the resultant model parameters representing systemic clearance of nicotine and cotinine for adolescent monkeys were approximately two- to three-fold of the adult values on a per body weight basis. The nonhuman primate PBPK model in general captured experimental observations that were used for both model calibration and evaluation, with acceptable performance metrics for precision and bias. The model also identified differences in nicotine pharmacokinetics between adolescent and adult nonhuman primates which might also be present in humans.

5.
Nanoscale ; 11(42): 20274-20283, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31626264

RESUMO

We report a facile chemical technique for synthesizing nanotube-based hybrid materials for near-infrared-driven photocatalytic hydrogen (H2) production. Upconversion nanoparticles (UCNPs), NaYF4:Yb,Tm,Gd (NYFG) and NaYF4:Yb,Tm (NYF), were engineered on C3N4 nanotubes (C3N4 NTs) separately to construct heterojunction structures. With a UCNP loading content of 15 wt%, the NYFG/C3N4 NT heterojunction exhibits the highest H2 generation rate of 311.6 µmol g-1 with an apparent quantum efficiency of 0.80 ‰, about 1.4 times higher than that of the NYF/C3N4 NT nanocomposite under 980 nm laser irradiation. Comprehensive characterization reveals that the enhanced photocatalytic performance of the Gd doped nanostructure is attributed to the synergistic effect, stronger interaction, higher emission intensities, and faster charge transfer between the UCNPs and C3N4 NTs. Moreover, the steady-state and dynamic fluorescence spectra indicate that the energy from NYFG NPs was transferred to C3N4 NTs via a fluorescence-resonance energy-transfer process. Our work demonstrates the potential of developing near-infrared-responsive photocatalysts for energy and environmental applications.

6.
J Med Chem ; 62(20): 8953-8972, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31314518

RESUMO

As a member of the Janus (JAK) family of nonreceptor tyrosine kinases, TYK2 plays an important role in mediating the signaling of pro-inflammatory cytokines including IL-12, IL-23, and type 1 interferons. The nicotinamide 4, identified by a SPA-based high-throughput screen targeting the TYK2 pseudokinase domain, potently inhibits IL-23 and IFNα signaling in cellular assays. The described work details the optimization of this poorly selective hit (4) to potent and selective molecules such as 47 and 48. The discoveries described herein were critical to the eventual identification of the clinical TYK2 JH2 inhibitor (see following report in this issue). Compound 48 provided robust inhibition in a mouse IL-12-induced IFNγ pharmacodynamic model as well as efficacy in an IL-23 and IL-12-dependent mouse colitis model. These results demonstrate the ability of TYK2 JH2 domain binders to provide a highly selective alternative to conventional TYK2 orthosteric inhibitors.

7.
J Med Chem ; 62(20): 8973-8995, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31318208

RESUMO

Small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. The discovery of isoform selective JAK inhibitors that traditionally target the catalytically active site of this kinase family has been a formidable challenge. Our strategy to achieve high selectivity for TYK2 relies on targeting the TYK2 pseudokinase (JH2) domain. Herein we report the late stage optimization efforts including a structure-guided design and water displacement strategy that led to the discovery of BMS-986165 (11) as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. In addition to unprecedented JAK isoform and kinome selectivity, 11 shows excellent pharmacokinetic properties with minimal profiling liabilities and is efficacious in several murine models of autoimmune disease. On the basis of these findings, 11 appears differentiated from all other reported JAK inhibitors and has been advanced as the first pseudokinase-directed therapeutic in clinical development as an oral treatment for autoimmune diseases.

8.
J Control Release ; 308: 119-129, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31325471

RESUMO

Exosomes, which are nano-vesicles produced by most cell types, play an irreplaceable role in cell-cell communication. They are extracellular small vesicles that can delivery various cargos of DNA, RNAs, proteins, and lipids. Because exosomes have different secretory components under physiological conditions and pathological conditions, it has been extensively studied in the field of diseases as a therapeutic target, as a drug/gene delivery vector and as a novel cancer marker. Despite the great development in recent decades, there are still many obstacles to be overcome, for example, the separation method is not standardized with low yield and poor stability, which limit its medical application. This review mainly summarizes the main progresses of isolation and identification techniques, diversity function and medical application of exosomes in recent years.

9.
Sci Transl Med ; 11(502)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341059

RESUMO

TYK2 is a nonreceptor tyrosine kinase involved in adaptive and innate immune responses. A deactivating coding variant has previously been shown to prevent receptor-stimulated activation of this kinase and provides high protection from several common autoimmune diseases but without immunodeficiency. An agent that recapitulates the phenotype of this deactivating coding variant may therefore represent an important advancement in the treatment of autoimmunity. BMS-986165 is a potent oral agent that similarly blocks receptor-stimulated activation of TYK2 allosterically and with high selectivity and potency afforded through optimized binding to a regulatory domain of the protein. Signaling and functional responses in human TH17, TH1, B cells, and myeloid cells integral to autoimmunity were blocked by BMS-986165, both in vitro and in vivo in a phase 1 clinical trial. BMS-986165 demonstrated robust efficacy, consistent with blockade of multiple autoimmune pathways, in murine models of lupus nephritis and inflammatory bowel disease, supporting its therapeutic potential for multiple immune-mediated diseases.

10.
Phys Rev Lett ; 122(11): 113602, 2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30951338

RESUMO

An outstanding goal in quantum optics and scalable photonic quantum technology is to develop a source that each time emits one and only one entangled photon pair with simultaneously high entanglement fidelity, extraction efficiency, and photon indistinguishability. By coherent two-photon excitation of a single InGaAs quantum dot coupled to a circular Bragg grating bull's-eye cavity with a broadband high Purcell factor of up to 11.3, we generate entangled photon pairs with a state fidelity of 0.90(1), pair generation rate of 0.59(1), pair extraction efficiency of 0.62(6), and photon indistinguishability of 0.90(1) simultaneously. Our work will open up many applications in high-efficiency multiphoton experiments and solid-state quantum repeaters.

11.
Exp Cell Res ; 380(2): 124-130, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-30954576

RESUMO

Aberrant miR-629-5p expression in several cancer types has been reported. Nonetheless, its potential effect and mechanism of action on tumor growth and metastasis in hepatocellular carcinoma (HCC) have rarely been analyzed. In this study, we found that miR-629-5p was upregulated in HCC tissue samples as compared to matched adjacent-tissue samples. Overexpression of miR-629-5p promoted the proliferation, migration, and invasiveness of human HCC cells in vitro, whereas miR-629-5p knockdown reduced these parameters. Consistently, miR-629-5p overexpression accelerated tumor growth and metastasis in a nude mouse model. Mechanistically, miR-629-5p directly targeted the 3' untranslated region (3'UTR) of the secreted frizzled-related protein 2 (SFRP2) mRNA and suppressed its expression, resulting in the activation of ß-catenin. Inhibition of ß-catenin abrogated miR-629-5p-induced growth and invasiveness. Collectively, these results suggest that miR-629-5p activates ß-catenin signaling by downregulating SFRP2 and thus promotes the growth and metastasis of HCC. These data open up new prospects for HCC treatment.

12.
Clin Lab ; 65(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969075

RESUMO

BACKGROUND: This study aims to evaluate whether miR-22 could be used as a potential biomarker to screen breast cancer patients from healthy controls. This has never been explored. METHODS: Real time PCR analysis was carried out to explore the expression of serum miR-22 in breast cancer patients. Chi-square test was used for counting data. Log rank test was used for comparing survival curves. CoX regression model was used for univariate and multivariate prognosis analysis. In addition, we also evaluated the role of miR-22 on the migration capacity of MCF-7 cells using a wound healing assay. RESULTS: We found that low expression of miR-22 was significantly associated with late TNM stage, lymph node metastasis, local recurrence, and distant metastasis. Meanwhile, low expression of miR-22 was significantly associated with short survival and poor prognosis in all patients and lymph node subgroups. Analysis of CoX univariate and multivariate models demonstrated that miR-22 is an independent prognostic marker of breast cancer. In ad-dition, overexpression of miR-22 significantly decreased the migration of MCF-7 cells, validating the tumor suppressor role of miR-22 in breast cancer cells. CONCLUSIONS: In summary, low miR-22 expression may be a potential biomarker to screen breast cancer patients from healthy control.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/diagnóstico , MicroRNAs/sangue , Adulto , Idoso , Linhagem Celular Tumoral , Movimento Celular , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Cicatrização , Adulto Jovem
13.
Nat Commun ; 10(1): 1131, 2019 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-30850594

RESUMO

Identification of gas molecules plays a key role a wide range of applications extending from healthcare to security. However, the most widely used gas nano-sensors are based on electrical approaches or refractive index sensing, which typically are unable to identify molecular species. Here, we report label-free identification of gas molecules SO2, NO2, N2O, and NO by detecting their rotational-vibrational modes using graphene plasmon. The detected signal corresponds to a gas molecule layer adsorbed on the graphene surface with a concentration of 800 zeptomole per µm2, which is made possible by the strong field confinement of graphene plasmons and high physisorption of gas molecules on the graphene nanoribbons. We further demonstrate a fast response time (<1 min) of our devices, which enables real-time monitoring of gaseous chemical reactions. The demonstration and understanding of gas molecule identification using graphene plasmonic nanostructures open the door to various emerging applications, including in-breath diagnostics and monitoring of volatile organic compounds.

14.
Int J Biol Macromol ; 131: 378-386, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30851326

RESUMO

The desmosome is a member of intercellular junctions that named 'anchoring junction', which contributes to the integrity and homeostasis of tissue structure and function of multicellular living organisms. As an important component of the desmosome and the most widely distributed isoform of desmocollins (DSCs), desmocollin2 (DSC2) has been demonstrated to be essential for the unity of epithelial cells, and served as a vital regulator in signaling processes such as epithelial morphogenesis, differentiation, wound healing, cell apoptosis, migration, and proliferation. Recent studies suggested that the aberrant expression or disruption of DSC2 might lead to some disorders, including heart disorders, certain cancers, and some other human diseases. The distinctions in expression and regulation mechanisms of DSC2 in different human diseases provided a potential target for diagnosis and individualized treatment. Further research is required to certify the signaling capacity of DSC2 and to shed light on the down-stream consequences of the signaling for us to understand the new area of DSC2 biology and the development of certain diseases. This review summarizes the molecular structure and dynamics of desmosome and DSC2, the relationship between the disruption or aberrant expression of DSC2 and human diseases and related molecular mechanisms, as well as the possible prospects.


Assuntos
Desmocolinas/genética , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Animais , Cálcio/metabolismo , Desmocolinas/química , Desmocolinas/metabolismo , Desmossomos/genética , Desmossomos/metabolismo , Humanos , Mutação , Transporte Proteico , Transdução de Sinais , Relação Estrutura-Atividade
15.
J Med Chem ; 62(5): 2265-2285, 2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30785748

RESUMO

Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P1 receptor modulator. In comparison to fingolimod (1), a full agonist of S1P1 currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life ( T1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P1. Herein, we describe our efforts to discover highly potent, partial agonists of S1P1 with a shorter T1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

16.
Gene ; 697: 144-151, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-30802542

RESUMO

ß-1,3-Glucan recognition protein (ßGRP) is an important pattern recognition protein, which could trigger immune response to eliminate pathogens by identifying and combining the pathogenic bacteria. In the present study, a ß-1,3-glucan recognition protein gene (ApßGRP) was cloned from a desert beetle Anatolica polita based on the EST sequence of ApßGRP in the suppression subtractive cDNA library. Quantitative real-time PCR (qRT-PCR) results showed that ApßGRP transcript in A. polita was significantly upregulated under the challenge of Escherichia coli and Staphylococcus aureus. Western blot analysis indicated that recombinant ApßGRP expressed in E. coli BL21, has the ability of binding to E. coli and S. aureus. Moreover, agglutination assay suggested that recombinant ApßGRP could agglutinate E. coli, S. aureus and Saccharomyces cerevisiae. The predicted 3D structure showed that ApßGRP possesses a typical ß-glucan recognition domain with seven ß-strands structures and conserved amino acid sequence. These data indicate that ApßGRP may be involved in immune defense in A. polita and could recognize and bind the bacteria against the invasion of external pathogens.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Besouros/genética , Lectinas/genética , Lectinas/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Escherichia coli/patogenicidade , Glucanos , Proteínas de Insetos/genética , Ligação Proteica , Staphylococcus aureus/patogenicidade , Regulação para Cima , beta-Glucanas/imunologia , beta-Glucanas/metabolismo
17.
Nanoscale ; 11(6): 2703-2709, 2019 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-30672542

RESUMO

Two-dimensional van der Waals (vdW) materials have a full set of highly confined polariton modes, such as low-loss phonon polaritons and dynamically tunable graphene plasmons, which provide a solution for integrated nanophotonic devices by combining the unique advantages of different polaritons. Highly efficient coupling between these complementary polaritons is key to realize the nanoscale optical integration. However, fluctuations of permittivity or geometry at the abrupt interfaces have been demonstrated as perturbations or scatters of polaritons. Here, in-plane plasmon-phonon polariton coupling in an in-plane graphene/hexagonal boron nitride (BN) heterostructure is studied using a full-wave electromagnetic numerical model. Transmittance between different polaritons is proportional to momentum matching, which can be tuned using the graphene Fermi energy. The transmittance between a graphene plasmon and a BN phonon polariton can be controlled between 0% and 100% within the upper Reststrahlen band of the BN. This is central to many photon devices, such as waveguides, wavefront shapers, filters, modulators and switches. Moreover, we simulate near-field interference patterns in an in-plane heterostructure based on the theoretical dispersion relation of polaritons, enabling scattering scanning near-field optical microscopy a potential experimental method to investigate the coupling between different polaritons. This study provides a theoretical basis for efficient coupling of propagation and modulation between different polaritons in in-plane heterostructures of vdW materials, which could pave a way to design nanoscale multi-functional waveguide devices in integrated photonic systems.

18.
Gene ; 690: 21-29, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30593914

RESUMO

Peptidoglycan recognition proteins (PGRPs) widely distributed in invertebrates and vertebrates are pattern-recognition molecules in innate immunity. In the present study, a novel short PGRP gene, designated as ApPGRP was identified from Anatolica polita. The deduced amino acid sequence of ApPGRP is composed of 196 residues and contains a conserved PGRP domain at the C-terminus. The phylogenetic tree showed that ApPGRP shared high homology of amino acid sequence with TcPGRP2 from Tribolium castaneum. The recombinant protein of ApPGRP exhibited binding activity toward Escherichia coli and DAP-type PGN from E. coli. Quantitative real time PCR (RT-qPCR) analysis indicated that the relative expression level of ApPGRP was up-regulated significantly after E. coli and DAP-type PGN challenge in the fifth instar larvae of A. polita. Moreover, the expressions of three antimicrobial peptides (AMPs) (ApAttacin 1, ApAttacin 2 and ApColeoptericin) were significantly increased after E. coli and DAP-type PGN challenge. RNA interference (RNAi) experiments showed that the expressions of three AMPs in the larvae of A. polita were significantly decreased after injection of ApPGRP dsRNA. Furthermore, the expressions of three AMPs in the larvae injected were still significantly decreased after E. coli challenge compared to the control samples without dsRNA injection. The predicted 3D structure showed that the ApPGRP could form the protein core of five ß-sheet and three ɑ-helices, which would be involved in specific PGN recognition. These results suggested that ApPGRP may play an important role in the immune response to E. coli infection and function as a receptor for antimicrobial peptide gene induction in Anatolica polita.


Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Escherichia coli/patogenicidade , Tenebrio/microbiologia , Regulação para Cima , Animais , Sequência de Bases , Proteínas de Transporte/química , Clonagem Molecular , Escherichia coli/imunologia , Evolução Molecular , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Modelos Moleculares , Filogenia , Estrutura Secundária de Proteína , Tenebrio/genética , Tenebrio/metabolismo
19.
Ann Neurol ; 84(5): 717-728, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30295338

RESUMO

OBJECTIVE: The present study was undertaken to determine the efficacy of coadministration of fingolimod with alteplase in acute ischemic stroke patients in a delayed time window. METHODS: This was a prospective, randomized, open-label, blinded endpoint clinical trial, enrolling patients with internal carotid artery or middle cerebral artery proximal occlusion within 4.5 to 6 hours from symptom onset. Patients were randomly assigned to receive alteplase alone or alteplase with fingolimod. All patients underwent pretreatment and 24-hour noncontrast computed tomography (CT)/perfusion CT/CT angiography. The coprimary endpoints were the decrease of National Institutes of Health Stroke Scale scores over 24 hours and the favorable shift of modified Rankin Scale score (mRS) distribution at day 90. Exploratory outcomes included vessel recanalization, anterograde reperfusion, and retrograde reperfusion of collateral flow. RESULTS: Each treatment group included 23 patients. Compared with alteplase alone, patients receiving fingolimod plus alteplase exhibited better early clinical improvement at 24 hours and a favorable shift of mRS distribution at day 90. In addition, patients who received fingolimod and alteplase exhibited a greater reduction in the perfusion lesion accompanied by suppressed infarct growth by 24 hours. Fingolimod in conjunction with alteplase significantly improved anterograde reperfusion of downstream territory and prevented the failure of retrograde reperfusion from collateral circulation. INTERPRETATION: Fingolimod may enhance the efficacy of alteplase administration in the 4.5- to 6-hour time window in patients with a proximal cerebral arterial occlusion and salvageable penumbral tissue by promoting both anterograde reperfusion and retrograde collateral flow. These findings are instructive for the design of future trials of recanalization therapies in extended time windows. Ann Neurol 2018;84:725-736.

20.
Biosci Rep ; 38(6)2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30341244

RESUMO

OBJECTIVE: To compare the efficacy and safety of rivaroxaban, apixaban and enoxaparin for thromboprophylaxis after arthroplastic surgery. METHODS: We conducted a meta-analysis containing a wide range of randomized controlled trials about efficiency and safety of rivaroxaban, apixaban and enoxaparin for thromboprophylaxis after arthroplastic surgery in the recent decade from January 2006 to June 2018. The present study separately analyzed the following key components: the different efficiency and safety for rivaroxaban and enoxaparin; apixaban and enoxaparin; and enoxaparin and other new developed anticoagulants. RESULTS: Sixteen studies containing 58885 patients were included. In results of efficacy outcomes, total events occurred in 4.89% patients of rivaroxaban group and 9.55% patients of the control group; however, no significant difference was observed in apixaban groups of their efficacy outcomes. Primary events didn't show significant difference when comparing apixaban with the control or comparing enoxaparin with the control. In analysis of safety outcomes, bleeding events occurred in 3.41% patients of rivaroxaban group compared with 2.84% patients of the control groups; bleeding events in apixaban groups were 4.09% compared with the control groups 4.64%. Bleeding events occurred in 3.51% patients of enoxaparin group, slightly lower than 5.82% of the control group. CONCLUSION: Direct oral anticoagulant, rivaroxaban might have better efficacy outcomes in thromboprophylaxis after arthroplastic surgery; however, apixaban showed no significantly different efficacy outcomes compared with enoxaparin, and enoxaparin may have equal or even better safety outcomes compared with direct oral anticoagulants.

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