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1.
Opt Express ; 27(21): 29676-29684, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684225

RESUMO

Laser wakefield accelerators have emerged as a promising candidate for compact synchrotron radiation and even x-ray free electron lasers. Today, to make the electrons emit electromagnetic radiation, the trajectories of laser wakefield accelerated electrons are deflected by transverse wakefield, counter-propagating laser field or external permanent magnet insertion device. Here, we propose a novel type of undulator that has a period of a few hundred microns and a magnetic field of tens of Tesla. The undulator consists of a bifilar capacitor-coil target that sustains a strong discharge current that generates a helical magnetic field around the coil axis when irradiated by a high-energy laser. Coupling this undulator with state-of-the-art laser wakefield accelerators can, simultaneously, produce ultra-bright quasi-monochromatic x-rays with tunable energy ranging 5-250 keV and optimize the free electron laser parameter and gain length compared with a permanent magnet-based undulator. This concept may pave a path toward ultra-compact synchrotron radiation and even x-ray free electron lasers.

2.
J Sep Sci ; 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31654547

RESUMO

As a representative formulation of Radix Salviae miltiorrhizae (Danshen)-Lignum Dalbergiae odoriferae (Jiangxiang), Xiangdan injection is widely prescribed for cardio- and cerebrovascular diseases in practice. This necessitates a pharmacokinetic investigation of this formulation to make it safer and more broadly applicable. We developed and validated a sensitive, selective and reliable HPLC-MS/MS method for simultaneous determination of eleven phenolic compounds including danshensu plus two diterpenoid quinones like cryptotanshinone and tanshinone IIA in rat. We applied this method for the pharmacokinetic studies of the thirteen compounds in a rat model of middle cerebral artery occlusion after intravenous injection of Xiangdan injection or Danshen injection. In sham-operated rats, the animals taking Xiangdan injection exhibited significant growth of the area under the curve for danshensu, protocatechuic aldehyde and tanshinone IIA compared with the changes seen in the data of those administrated with Danshen injection. Such a pattern was also observed in middle cerebral artery occlusion rats, whereas increased the area under the curve values were observed for danshensu, protocatechuic aldehyde, caffeic acid, rosmarinic acid and tanshinone IIA. These results demonstrated that synergistic interactions occurred between the components of Danshen and the active compounds of Jiangxiang both in sham-operated and middle cerebral artery occlusion rats, increasing the bioavailability of Danshen. The results presented herein can be used to determine a reference dose for the clinical application of Xiangdan injection, and to elucidate the synergistic mechanism of Danshen and Jiangxiang. This article is protected by copyright. All rights reserved.

3.
Phytomedicine ; 62: 152948, 2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31129431

RESUMO

BACKGROUND: Huangqi decoction (HQD), a classic traditional herbal medicine, has been used for liver fibrosis, but its effect on intrahepatic chronic cholestatic liver injury remains unknown. PURPOSE: In the present study, we investigated the hepatoprotective effect of HQD and the underlying molecular mechanisms in 3, 5-diethoxycarbonyl-1, 4-dihydroxychollidine (DDC)-induced chronic cholestatic mice. METHODS: The DDC-induced cholestatic mice were administrated HQD for 4 or 8 weeks. Serum biochemistry and morphology were investigated. The serum and liver bile acid (BA) levels were detected by ultra performance liquid chromatography-tandem mass spectrometry. The liver expression of BA metabolizing enzymes and transporters, and inflammatory and fibrotic markers was measured by real-time polymerase chain reaction, western blotting, and immunohistochemistry. RESULTS: HQD treatment for 4 or 8 weeks ameliorated DDC-induced liver injury by improving impaired hepatic function and tissue damage. HQD treatment for 8 weeks further decreased the liver expression of cytokeratin 19, tumor growth factor (TGF)-ß, collagen I, and α-smooth muscle actin, and ameliorated ductular reaction and liver fibrosis. HQD markedly decreased the accumulation of serum and liver BA. The expression of BA-metabolizing enzymes, cytochrome P450 2b10 and UDP glucuronosyltransferase 1 A1, and multidrug resistance-associated protein 2, Mrp3, and Mrp4 involved in BA homeostasis was increased by 4 weeks of HQD treatment. The expression of BA uptake transporter Na+-taurocholate cotransporting polypeptide was decreased and that of Mrp4 was increased after 8 weeks of HQD treatment. Nuclear factor-E2-related factor-2 (Nrf2) was remarkably induced by HQD treatment. Additionally, HQD treatment for 8 weeks decreased the liver expression of inflammatory factors, interleukin (IL)-6, IL-1ß, tumor necrosis factor-α, monocyte chemoattractant protein-1, and intracellular adhesion molecule-1. HQD suppressed the nuclear factor (NF)-κB pathway. CONCLUSION: HQD protected mice against chronic cholestatic liver injury and biliary fibrosis, which may be associated with the induction of the Nrf2 pathway and inhibition of the NF-κB pathway, ameliorating BA-stimulated inflammation.

4.
Biomed Pharmacother ; 115: 108906, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31060007

RESUMO

Both aspirin and vicagrel are effective antiplatelet drugs, with the potential for concomitant use as another dual-antiplatelet therapy for the prevention of recurrent thrombotic or ischemic events. Because they both are the substrates of carboxylesterase 2 (CES2), aspirin attenuated the metabolic activation of and platelet response to vicagrel in mice treated with the two drugs concomitantly. In this study, we sought to clarify whether vicagrel could affect platelet responses to aspirin and their underlying mechanisms. Plasma levels of aspirin and salicylic acid were determined by liquid chromatography-tandem mass spectrometry, inhibition of arachidonic acid (AA)-induced whole-blood platelet aggregation by aspirin was assessed with an aggregometer, and their antithrombotic effects were evaluated by arteriovenous shunt thrombosis model. The results showed that concomitant use of vicagrel (5, 10, or 20 mg/kg) led to an average of 55% and 77% increases in systemic exposure of aspirin (Cmax and AUC0-t) and 2.8-fold increase in suppression of AA-induced platelet aggregation in mice when compared with use of aspirin alone. In the rat thrombus formation model, vicagrel (1 mg/kg) enhanced inhibition of thrombosis formation by aspirin (5 mg/kg), but not vice versa. We conclude that vicagrel increases platelet responses to aspirin and also enhances inhibition of thrombus formation of aspirin due to decreased CES2-catalyzed aspirin inactivation in rodents, and that an integrated net effect on thrombus formation in vivo is superior to inhibition of AA- or ADP-induced platelet aggregation ex vivo by either of the two drugs if taken concomitantly.

5.
Br J Pharmacol ; 176(11): 1717-1727, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30825385

RESUMO

BACKGROUND AND PURPOSE: Vicagrel is a novel promising antiplatelet drug designed for overcoming clopidogrel resistance. There is limited evidence indicating that exogenous IL-10 suppresses CYP3A4 activity in healthy subjects and that IL-10 knockout (KO) mice exhibit increased clopidogrel bioactivation compared with wild-type (WT) mice. In this study, we sought to determine whether IL-10 could play an important role in the metabolism of and platelet response to vicagrel in mice. EXPERIMENTAL APPROACH: IL-10 KO and WT mice were administered vicagrel, then their plasma H4 (active metabolite of vicagrel) concentrations were determined by LC-MS/MS, and inhibition of ADP-induced whole-blood platelet aggregation by vicagrel was assessed with an aggregometer. The mRNA and protein levels of several relevant genes between IL-10 KO and WT mice were measured by qRT-PCR and Western blots, respectively. Intestinal Aadac protein levels were measured in IL-10 WT mice injected i.p. with vehicle control, Stattic, or BAY 11-7082. KEY RESULTS: Compared with WT mice, IL-10 KO mice exhibited significantly increased plasma levels of H4 and enhanced platelet responses to vicagrel, as well as significantly higher mRNA and protein levels of arylacetamide deacetylase (Aadac) in the intestine. In WT mice, STAT3, not NF-κB, mediated Aadac expression in the intestine. CONCLUSIONS AND IMPLICATIONS: IL-10 suppresses metabolic activation of vicagrel through down-regulation of Aadac in mouse intestine in a STAT3-dependent manner and, consequently, attenuates platelet responses to vicagrel, suggesting that the antiplatelet effect of vicagrel may be modulated by changes in plasma IL-10 levels in relevant clinical settings.

6.
Chin Med J (Engl) ; 131(17): 2080-2088, 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30127218

RESUMO

Background: Valproic acid (VPA) exposure during pregnancy has been proven to contribute to congenital heart disease (CHD). Our previous findings implied that disruption of planar cell polarity (PCP) signaling pathway in cardiomyocytes might be a factor for the cardiac teratogenesis of VPA. In addition, the teratogenic ability of VPA is positively correlated to its histone deacetylase (HDAC) inhibition activity. This study aimed to investigate the effect of the VPA on cardiac morphogenesis, HDAC1/2/3, and PCP key genes (Vangl2/Scrib/Rac1), subsequently screening out the specific HDACs regulating PCP pathway. Methods: VPA was administered to pregnant C57BL mice at 700 mg/kg intraperitoneally on embryonic day 10.5. Dams were sacrificed on E15.5, and death/absorption rates of embryos were evaluated. Embryonic hearts were observed by hematoxylin-eosin staining to identify cardiac abnormalities. H9C2 cells (undifferentiated rat cardiomyoblasts) were transfected with Hdac1/2/3 specific small interfering RNA (siRNA). Based on the results of siRNA transfection, cells were transfected with Hdac3 expression plasmid and subsequently mock-treated or treated with 8.0 mmol/L VPA. Hdac1/2/3 as well as Vangl2/Scrib/Rac1 mRNA and protein levels were determined by real-time quantitative polymerase chain reaction and Western blotting, respectively. Total HDAC activity was detected by colorimetric assay. Results: VPA could induce CHD (P < 0.001) and inhibit mRNA or protein expression of Hdac1/2/3 as well as Vangl2/Scrib in fetal hearts, in association with total Hdac activity repression (all P < 0.05). In vitro, Hdac3 inhibition could significantly decrease Vangl2/Scrib expression (P < 0.01), while knockdown of Hdac1/2 had no influence (P > 0.05); VPA exposure dramatically decreased the expression of Vanlg2/Scrib together with Hdac activity (P < 0.01), while overexpression of Hdac3 could rescue the VPA-induced inhibition (P > 0.05). Conclusion: VPA could inhibit Hdac1/2/3, Vangl2/Scrib, or total Hdac activity both in vitro and in vivo and Hdac3 might participate in the process of VPA-induced cardiac developmental anomalies.

7.
Huan Jing Ke Xue ; 39(7): 3212-3221, 2018 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-29962145

RESUMO

Niobate-modified titanate nanosheets (Nb-TNS) were synthesized through a hydrothermal method and used to remove Cd(Ⅱ) from water. TEM and SEM characterizations indicated that the new nanocomposites were non-curled nanosheets. XRD showed that the material was composed of sodium tri-titanate and niobate, and titanate was the primary component. Ion exchange between Cd2+ and Na+ in the interlayers of the Nb-TNSs was the dominant mechanism for Cd(Ⅱ) adsorption, leading to good adsorption performance. The material exhibited rapid adsorption kinetics for Cd(Ⅱ), reaching equilibrium within 60 min, and the data fit well with the pseudo-second order model (R2=1). The maximum adsorption capacity of Cd(Ⅱ) was 287.9 mg·g-1, according to the Langmuir isotherm model, which was larger than that of most of traditional adsorbents. Higher pH promoted adsorption because the negatively charged material could capture Cd(Ⅱ) cations more easily. Co-existing inorganic ions (Na+and Ca2+) were unfavorable to the adsorption of Cd(Ⅱ) by Nb-TNS owing to the competition for adsorption sites. In addition, a slight inhibition effect on the adsorption in the presence of humic acid (HA) was found. Cd(Ⅱ) was efficiently desorbed from Nb-TNS after HNO3 treatment, and -ONa sites were restored with NaOH treatment. Considering its simple synthesis method, high removal efficiency for heavy metals, and good reusability, Nb-TNS is a promising material for remediation of areas contaminated by heavy metals.

8.
Sci Total Environ ; 625: 64-70, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29289007

RESUMO

In this study, impacts of nanoplastic on the pure and mixed anaerobic digestion systems were investigated. Results showed the growth and metabolism of Acetobacteroides hydrogenigenes were partly inhibited by nanoplastic existed in the pure anaerobic digestion system. The anaerobic digestion of sewage sludge was also obviously inhibited by nanoplastic existed in the mixed anaerobic digestion system. Both the methane yield and methane production rate of the mixed anaerobic digestion system showed negative correlation with the nanoplastic concentration. Compared with anaerobic digestion system without nanoplastic, methane yield and maximum daily methane yield at the nanoplastic concentration of 0.2g/L decreased for 14.4% and 40.7%, respectively. In addition, the start-up of mixed anaerobic digestion system was prolonged by addition of nanoplastic. Microbial community structure analysis indicated the microbial community structures were also affected by nanoplastic existed in the system. At the nanoplastic concentration of 0.2g/L, the relative abundances of family Cloacamonaceae, Porphyromonadaceae, Anaerolinaceae and Gracilibacteraceae decreased partly. Conversely, the relative abundances of family Anaerolinaceae, Clostridiaceae, Geobacteraceae, Dethiosulfovibrionaceae and Desulfobulbaceae improved partly.

9.
Huan Jing Ke Xue ; 39(12): 5672-5679, 2018 Dec 08.
Artigo em Chinês | MEDLINE | ID: mdl-30628414

RESUMO

A rice pot experiment was conducted to investigate the effect of phosphorus addition on the abundance of autotrophic CO2-fixation microorganisms using phosphorus-limited paddy soil from the Changsha Observation and Research Station for the Agricultural Environment. Rice seedlings were transplanted in the paddy soil with or without phosphorus addition, corresponding to P-treated-pot (P) or control pot (CK), respectively. Rhizosphere soils were collected from the P and CK treatments during the tillering and shooting stages. The physical and chemical soil properties were measured and the abundance of autotrophic CO2-fixation microorganisms was quantified with a real-time PCR technique based on four functional genes (cbbL, cbbM, accA, and aclB) involved in three CO2-fixation pathways (CBB cycle, rTCA cycle, and 3-hydroxypropionate/4-hydroxybutyrate cycle). The results show that phosphorus addition improves the concentrations of DOC and Olsen-P and the pH value, whereas negative effects on the MBC and NH4+-N concentrations are revealed during the tillering stage. The effect of phosphorus addition on the NO3--N concentration in the tillering and shooting stages differs. Phosphorus addition significantly increases the abundances of the cbbL, cbbM, accA, and aclB genes, which are 156%, 99%, 110%, and 193% higher than those of the CK treatment in the tillering stage. However, this positive effect is not notable for the cbbL, accA, and aclB genes during the shooting stage. Redundancy analysis (RDA) shows that Olsen-P is the environmental factor that most significantly affects the abundance of autotrophic CO2-fixation microorganisms.


Assuntos
Dióxido de Carbono/química , Fósforo/química , Microbiologia do Solo , Solo/química , Bactérias , Fertilizantes , Oryza , Rizosfera , Ribulose-Bifosfato Carboxilase
10.
Oncotarget ; 8(57): 97137-97152, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29228599

RESUMO

This study explored the effects of chicken bile powder (CBP), a 2000-year-old Chinese medicine, on α-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. CBP treatment for 14 days significantly ameliorated ANIT-induced changes in serum alanine aminotransferase, aspartate aminotransferase, bile acids, bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase, and liver tissue morphology. Serum metabolomics showed changes in 24 metabolites in ANIT-exposed mice; 16 of these metabolites were reversed by CBP treatment via two main pathways (bile acid biosynthesis and arachidonic acid metabolism). Additionally, CBP administration markedly increased fecal and biliary bile acid excretion, and reduced total and hydrophobic bile acid levels in the livers of cholestatic mice. Moreover, CBP increased liver expression of bile acid efflux transporters and metabolic enzymes. It also attenuated ANIT-induced increases in hepatic nuclear factor-κB-mediated inflammatory signaling, and increased liver expression of the nuclear farnesoid X receptor (FXR) in cholestatic mice. CBP also activated FXR in vitro in HEK293T cells expressing mouse Na+-taurocholate cotransporting polypeptide. It did not ameliorate the ANIT-induced liver injuries in FXR-knockout mice. These results suggested that CBP provided protection from cholestatic liver injury by restoring bile acid homeostasis and reducing inflammation in a FXR-dependent manner.

11.
Oncol Lett ; 14(2): 2165-2169, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28789441

RESUMO

The aim of the study was to investigate the expression and clinical significance of early growth response protein 1 (EGR-1) and phosphatase and tensin homolog (PTEN) in the pituitary tumors of elderly patients. From January 2014 to December 2015, we collected 25 patient cases with non-invasive pituitary tumors, 10 cases with invasive pituitary tumors and 35 cases with healthy pituitary tissues (the healthy control group). Immunohistochemical staining was used to detect the expression of EGR-1 and PTEN, and analyze specific differences. The expression of EGR-1 and PTEN in patients with invasive and non-invasive pituitary tumors increased significantly, when compared with the healthy control group, and the difference was statistically significant (p<0.05). In patients with invasive tumors, EGR-1 levels were higher than levels in patients with non-invasive tumors. The difference was statistically significant (p<0.05). PTEN levels in patients with invasive tumors were significantly lower than levels in patients with non-invasive tumors. The difference was statistically significant (p<0.05). In conclusion, EGR-1 and PTEN levels in patients with pituitary tumors were significantly higher. In addition, EGR-1 levels were higher in patients with invasive pituitary tumors, while PTEN levels were lower. The combination of increases in both levels highlights an important role in the evaluation and prognosis of elderly patients with pituitary tumors.

12.
Chin Med J (Engl) ; 130(11): 1352-1360, 2017 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-28524836

RESUMO

BACKGROUND: Placental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process. METHODS: The human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 µmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively. RESULTS: TSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 µmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 µmol/L, P = 0.001 for 3.0 µmol/L, and P < 0.001 for 5.0 µmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001). CONCLUSIONS: HDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Trofoblastos/citologia , Trofoblastos/metabolismo , Linhagem Celular , Histona Desacetilase 1/metabolismo , Histona Desacetilase 2/metabolismo , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Microscopia de Fluorescência , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , RNA Mensageiro
13.
Cytotechnology ; 69(5): 775-783, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28365799

RESUMO

Displaying a protein on the surface of cells has been provided a very successful strategy to function research of exogenous proteins. Based on the membrane fusion characteristic of Autographa californica multiple nucleopolyhedrovirus envelope protein GP64, we amplified and cloned N-terminal signal peptide and C-terminal transmembrane domain as well as cytoplasmic tail domain of gp64 gene into vector pIZ/V5-His with multi-cloning sites to construct the cell surface expression vector pIZ/V5-gp64. To verify that the vector can be used to express proteins on the membrane of insect cells, a recombinant plasmid pIZ/V5-gp64-GFP was constructed by introducing the PCR amplified green fluorescent protein (GFP) gene and transfected into insect cell lines Sf9 and H5. The transected cells were screened with zeocin and cell cloning. PCR verification results showed that the GFP gene was successfully integrated into these cells. Green fluorescence in Sf9-GFP and H5-GFP cells was observed by using confocal laser scanning microscopy and immunofluorescence detection indicated that GFP protein was located on the cell membrane. Western blot results showed that a fusion protein GP64-GFP of about 40 kDa was expressed on the membrane of Sf9-GFP and H5-GFP cells. The expression system constructed in this paper can be used for localization and continuous expression of exogenous proteins on insect cell membrane.

14.
Front Pharmacol ; 8: 938, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29311939

RESUMO

Intrahepatic cholestasis is a serious symptom of liver disorders with limited therapies. In this study, we investigated the efficacy of Huangqi decoction (HQD), a two-herb classic traditional Chinese medicine (TCM), in the treatment of alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. HQD treatment ameliorated impaired hepatic function and tissue damage. A metabolomics study revealed that the endogenous metabolites significantly affected by HQD were related to bile acid (BA) biosynthesis and glutathione metabolism pathways. HQD treatment decreased the intrahepatic accumulation of cytotoxic BAs, normalized serum BA levels, and increased biliary and urinary BA excretion. Additionally, HQD restored the hepatic glutathione content and suppressed reactive oxygen species (ROS) in cholestatic mice. Protein and gene analysis revealed that HQD increased the expression of the hepatic metabolizing enzymes cytochrome P450 (CYP) 2B10 and UDP glucuronosyltransferase family 1 member A1 (UGT1A1), as well as multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4, which play crucial roles in BA homeostasis. Further, HQD increased the protein expression of glutamate-cysteine ligase, which is involved in the synthesis of glutathione. Importantly, HQD increased the nuclear expression of nuclear factor-E2-related factor-2 (Nrf2). In conclusion, HQD protects against intrahepatic cholestasis by reversing the disordered homeostasis of BAs and glutathione.

15.
Virus Res ; 220: 172-8, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27157859

RESUMO

Multigene-armed oncolytic adenoviruses are capable of efficiently generating a productive antitumor immune response. The chemokine (C-C motif) ligand 21 (CCL21) binds to CCR7 on naïve T cells and dendritic cells (DCs) to promote their chemoattraction to the tumor and resultant antitumor activity. Interleukin 21 (IL21) promotes survival of naïve T cells while maintaining their CCR7 surface expression, which increases their capacity to transmigrate in response to CCL21 chemoattraction. IL21 is also involved in NK cell differentiation and B cell activation and proliferation. The generation of effective antitumor immune responses is a complex process dependent upon coordinated interactions of various subsets of effector cells. Using the AdEasy system, we aimed to construct an oncolytic adenovirus co-expressing CCL21 and IL21 that could selectively replicate in TERTp-positive tumor cells (Ad-CCL21-IL21 virus). The E1A promoter of these oncolytic adenoviruses was replaced by telomerase reverse transcriptase promoter (TERTp). Ad-CCL21-IL21 was constructed from three plasmids, pGTE-IL21, pShuttle-CMV-CCL21 and AdEasy-1 and was homologously recombined and propagated in the Escherichia coli strain BJ5183 and the packaging cell line HEK-293, respectively. Our results showed that our targeted and armed oncolytic adenoviruses Ad-CCL21-IL21 can induce apoptosis in TERTp-positive tumor cells to give rise to viral propagation, in a dose-dependent manner. Importantly, we confirm that these modified oncolytic adenoviruses do not replicate efficiently in normal cells even under high viral loads. Additionally, we investigate the role of Ad-CCL21-IL21 in inducing antitumor activity and tumor specific cytotoxicity of CTLs in vitro. This study suggests that Ad-CCL21-IL21 is a promising targeted tumor-specific oncolytic adenovirus.


Assuntos
Adenoviridae/genética , Proteínas E1A de Adenovirus/genética , Quimiocina CCL21/genética , Interleucinas/genética , Vírus Oncolíticos/genética , Telomerase/genética , Adenoviridae/imunologia , Proteínas E1A de Adenovirus/imunologia , Células CACO-2 , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Quimiocina CCL21/imunologia , Técnicas de Cocultura , Células Epiteliais/citologia , Células Epiteliais/imunologia , Escherichia coli/genética , Escherichia coli/metabolismo , Células HEK293 , Células HT29 , Células HeLa , Recombinação Homóloga , Humanos , Interleucinas/imunologia , Masculino , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/imunologia , Plasmídeos/química , Plasmídeos/imunologia , Próstata/citologia , Próstata/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Células THP-1 , Telomerase/imunologia
16.
World J Pediatr ; 12(3): 298-307, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27059744

RESUMO

BACKGROUND: There is no consensus on the effectiveness of prenatal diagnosis except for hospitalized outcomes. Hence, a meta-analysis of published literature was conducted to assess the effect of prenatal diagnosis. METHODS: Literature review has identified relevant studies up to December 2013. A meta-analysis was performed according to the guidelines from the Cochrane review group and the PRISMA statement. Studies were identified by searching PubMed, Embase, the Cochrane Central Register of Controlled Trials and World Health Orgnization clinical trials registry center. Meta-analysis was performed in a fixed/random-effect model using Revman 5.1.1 according to the guidelines from the Cochrane review group and the PRISMA guidelines. RESULTS: The results from 13 cohort studies in 12 articles were analyzed to determine the optimal treatment with the lower rate of perioperative mortality in prenatal diagnosis. The superiority of a prenatal diagnosis has been proven because the surgical procedure could be done in the early neonatal period (95% CI, -0.76, -0.40). The prenatal diagnosis has also remarkably reduced the preoperative and postoperative mortality rates in cases of transposition of the great arteries (95% CI=0.06, 0.80; 95% CI=0.01, 0.82, respectively), as well as the overall results with all subtypes (95% CI=0.18, 0.94; 95% CI=0.46, 0.94, respectively). CONCLUSIONS: Prenatal diagnosis is effective in perinatal management with an earlier intervention for major congenital heart disease, but only results in a reduced perioperative mortality in cases of transposition of the great arteries. Further investigations are required to evaluate the effect of prenatal diagnosis on life quality during a long-term follow-up.


Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Ecocardiografia/métodos , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/cirurgia , Mortalidade Perinatal/tendências , Diagnóstico Pré-Natal/métodos , Peso ao Nascer , Procedimentos Cirúrgicos Cardíacos/métodos , Feminino , Idade Gestacional , Cardiopatias Congênitas/mortalidade , Humanos , Lactente , Recém-Nascido , Masculino , Determinação de Necessidades de Cuidados de Saúde , Assistência Perioperatória/métodos , Cuidados Pós-Operatórios/métodos , Gravidez , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Análise de Sobrevida
17.
Front Neurosci ; 10: 33, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26909014

RESUMO

The cerebellum plays an essential role in balance and motor coordination. Purkinje cells (PCs) are the sole output neurons of the cerebellar cortex and are critical for the execution of its functions, including motor coordination. Toll-like receptor (TLR) 4 is involved in the innate immune response and is abundantly expressed in the central nervous system; however, little is known about its role in cerebellum-related motor functions. To address this question, we evaluated motor behavior in TLR4 deficient mice. We found that TLR4(-∕-) mice showed impaired motor coordination. Morphological analyses revealed that TLR4 deficiency was associated with a reduction in the thickness of the molecular layer of the cerebellum. TLR4 was highly expressed in PCs but not in Bergmann glia or cerebellar granule cells; however, loss of TLR4 decreased the number of PCs. These findings suggest a novel role for TLR4 in cerebellum-related motor coordination through maintenance of the PC population.

18.
J Zhejiang Univ Sci B ; 14(11): 961-72, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24190442

RESUMO

Orthotopic liver transplantation (OLT) is the only proven effective treatment for both end-stage and metabolic liver diseases. Hepatocyte transplantation is a promising alternative for OLT, but the lack of available donor livers has hampered its clinical application. Hepatocyte-like cells (HLCs) differentiated from many multi-potential stem cells can help repair damaged liver tissue. Yet almost suitable cells currently identified for human use are difficult to harvest and involve invasive procedures. Recently, a novel mesenchymal stem cell derived from human menstrual blood (MenSC) has been discovered and obtained easily and repeatedly. In this study, we examined whether the MenSCs are able to differentiate into functional HLCs in vitro. After three weeks of incubation in hepatogenic differentiation medium containing hepatocyte growth factor (HGF), fibroblast growth factor-4 (FGF-4), and oncostain M (OSM), cuboidal HLCs were observed, and cells also expressed hepatocyte-specific marker genes including albumin (ALB), α-fetoprotein (AFP), cytokeratin 18/19 (CK18/19), and cytochrome P450 1A1/3A4 (CYP1A1/3A4). Differentiated cells further demonstrated in vitro mature hepatocyte functions such as urea synthesis, glycogen storage, and indocyanine green (ICG) uptake. After intrasplenic transplantation into mice with 2/3 partial hepatectomy, the MenSC-derived HLCs were detected in recipient livers and expressed human ALB protein. We also showed that MenSC-derived HLC transplantation could restore the serum ALB level and significantly suppressed transaminase activity of liver injury animals. In conclusion, MenSCs may serve as an ideal, easily accessible source of material for tissue engineering and cell therapy of liver tissues.


Assuntos
Diferenciação Celular , Doença Hepática Terminal/terapia , Hepatócitos/citologia , Menstruação/sangue , Células-Tronco Mesenquimais/citologia , Animais , Separação Celular , Hepatócitos/transplante , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C
19.
Zhonghua Er Ke Za Zhi ; 51(8): 584-9, 2013 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-24225288

RESUMO

OBJECTIVE: To investigate the effect of different operation time to percutaneous balloon pulmonic valvuloplasty (PBPV) to critical pulmonary valve stenosis (CPS). METHOD: Twenty-one infants (age ≤ 60 days at operating day) suffered from CPS, diagnosed by fetal echocardiogram and confirmed by echocardiography after birth, were enrolled in this case-control-study with written informed consent during April 2007 to December 2011. Of the 21 cases, 7 had prenatal diagnosis in our prenatal diagnosis center (prenatal group, Pre) and 14 were referred from other hospitals, who were divided into postpartum group A (Post A, referred within 28 days after birth) and postpartum group B (Post B, referred 29 to 60 days after birth). To Pre-group, the integrative interventional protocol was cautiously made by the consultative specialists, including intrauterine diagnosis, perinatal care and urgent PBPV soon after birth. To Post-group, emergency PBPV was preformed after the referral. Tei index of right ventricular and pressure-gradient (PG) between right ventricular and pulmonary artery were measured before and at different time points one year after PBPV. RESULT: The values of SpO2 in Pre-group ranged from 82%-92% (86.57% ± 5.34%) under the state of continuous intravenous infusion of alprostadil. PBPV was successfully preformed within 3-6 days after birth. The values of SpO2 increased to 97.33% ± 1.15% post procedure. The values of PG pre- and post- procedure were (86.34 ± 11.77) mm Hg and (31.43 ± 8.46) mm Hg respectively. Preoperative RV Tei-index was 0.68 ± 0.05, it decreased rapidly after procedure, and recovered to normal one month after procedure. Only one case showed restenosis seven months after procedure and repeated PBPV. Fourteen referral cases (6 cases in Post A group and 8 cases in Post B group, accompanied in 1 and 3 cases with heart failure), the values of SpO2 ranged from 83%-91% under state of continuous intravenous infusion of alprostadil. And the operating time was 10-57 days after birth. The values of SpO2 recovered to normal post procedure, and heart failure alleviated. Increased preoperative RV pressure obviously decreased significantly post-procedure. And increased Tei-index declined gradually, at one-year follow-up, the value of Tei-index in Post A group recovered to normal, whereas that of Post B was (0.51 ± 0.06), compared to Pre and Post A groups, the difference was significant (P < 0.05) . One case showed restenosis nine months after procedure and repeated PBPV was performed. The hypoxic exposure durations were (4.43 ± 0.68) , (16.33 ± 4.46) , (41.25 ± 9.19) , respectively, and the difference among the three groups was significant (P < 0.05). CONCLUSION: To the fetuses with definite prenatal diagnosis of critical pulmonary valve stenosis, preoperative general condition can be adjusted to more suitable for emergency operation. Early PBPV can achieve shorter hypoxic exposure and better recovery of right ventricular function post procedure. Perinatal integrated intervention for CPS can significantly improve the prognosis and quality of life in this patient population.


Assuntos
Cateterismo/métodos , Diagnóstico Pré-Natal/métodos , Artéria Pulmonar/cirurgia , Estenose da Valva Pulmonar/diagnóstico , Estenose da Valva Pulmonar/cirurgia , Cateterismo/instrumentação , Dilatação/métodos , Ecocardiografia , Feminino , Humanos , Lactente , Recém-Nascido , Gravidez , Artéria Pulmonar/fisiopatologia , Estenose da Valva Pulmonar/congênito , Estenose da Valva Pulmonar/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Função Ventricular Direita
20.
Histol Histopathol ; 27(7): 897-903, 2012 07.
Artigo em Inglês | MEDLINE | ID: mdl-22648545

RESUMO

PaCO(2) is an important factor in the regulation of cerebral circulation, and it is often used to reduce intracranial pressure through hyperventilation during neurosurgery. Changes in concentration can cause changes in CBF (cerebral blood flow). 20-HETE is a product of CYP4A-mediated AA (arachidonic acid) metabolism and is a powerful endogenous vasoconstrictor; however, its effect on cerebral vasoconstriction in cats, dogs and rats remains to be confirmed. It is known that changes in PaCO(2) can influence the expression of CYP4A in the rat brain, demonstrating the important role of 20-HETE in the mechanism of CO(2)-mediated cerebrovascular reactivity. Thirty healthy adult male Wistar rats that weighed between 200 g and 250 g were randomly divided into three groups (A, B, and C; n=10): group A, normocapnia (PaCO(2) was maintained at approximately 40-45 mmHg); group B, hypocapnia (PaCO(2) was maintained at approximately 20-25 mmHg); and group C, hypercapnia (PaCO(2) was maintained at approximately 60-65 mmHg). Physiological parameters, including HR (heart rate), MBP(mean blood pressure), PH and PaCO(2) were recorded every 30 min, and there were no significant hemodynamic or body temperature differences. The head was removed after 3.5 h to investigate brain CYP4A by immunohistochemistry. Relative to group A, group B exhibited the following changes: an increased pH, decreased PaCO(2), and increased brain CYP4A protein expression (P<0.05). In contrast, group C exhibited decreased PH, increased PaCO(2) and decreased CYP4A protein expression (P<0.05). CO(2) can decrease the expression of brain CYP4A during hypercapnia and increase its expression during hypocapnia.


Assuntos
Encéfalo/enzimologia , Dióxido de Carbono/sangue , Circulação Cerebrovascular/fisiologia , Citocromo P-450 CYP4A/biossíntese , Hemodinâmica/fisiologia , Animais , Artérias/fisiologia , Encéfalo/irrigação sanguínea , Hipercapnia/metabolismo , Hipocapnia/metabolismo , Masculino , Pressão Parcial , Ratos , Ratos Wistar
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