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2.
Eur J Med Chem ; 187: 111914, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31806538

RESUMO

Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC50 = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC50 = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.

3.
Thorac Cancer ; 11(1): 103-112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31692283

RESUMO

BACKGROUND: Distinction in the mutational profile between the common histological types, lung adenocarcinoma (LUAD) and squamous cell lung carcinoma (LUSC) has been well-established. However, comprehensive mutation profiles of the predominant histological subtypes within LUAD and LUSC remains elusive. METHODS: We analyzed the mutational profile of 318 Chinese NSCLC patients of adenocarcinoma and squamous cell carcinoma predominant subtypes from seven hospitals using capture-based ultra-deep sequencing of 68 lung cancer-related genes. RESULTS: Of the 318 NSCLC patients, 215 were diagnosed with LUAD and 103 with LUSC. Adenocarcinoma in situ and acinar adenocarcinoma were the most predominant subtypes of LUAD. On the other hand, keratinizing squamous cell carcinoma was the most predominant subtype of LUSC. Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype. More than half of the patients with preinvasive adenocarcinoma in situ, minimally invasive, acinar, micropapillary and papillary subtypes were also EGFR-mutants. Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations. Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes. A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants. PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes. CONCLUSION: These data suggest that the mutational profiles among the predominant histological subtypes were very distinct, which provided a reliable tool to improve treatment decisions.

4.
Animals (Basel) ; 9(10)2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615062

RESUMO

Short-chain fatty acids (SCFAs) (a microbial fermentation production in the rabbit gut) have an important role in many physiological processes, which may be related to the reduced body fat of rabbits. In the present experiment, we study the function of acetate (a major SCFA in the rabbit gut) on fat metabolism. Ninety rabbits (40 days of age) were randomly divided into three groups: a sham control group (injection of saline for four days); a group experiencing subcutaneous injection of acetate for four days (2 g/kg BM per day, one injection each day, acetate); and a pair-fed sham treatment group. The results show that acetate-inhibited lipid accumulation by promoting lipolysis and fatty acid oxidation and inhibiting fatty acid synthesis. Activated G protein-coupled receptor 41/43, adenosine monophosphate activated protein kinase (AMPK) and extracellular-signal-regulated kinase (ERK) 1/2 signal pathways were likely to participate in the regulation in lipid accumulation of acetate. Acetate reduced hepatic triglyceride content by inhibiting fatty acid synthesis, enhancing fatty acid oxidation and lipid output. Inhibited peroxisome proliferator-activated receptor α (PPARα) and activated AMPK and ERK1/2 signal pathways were related to the process in liver. Acetate reduced intramuscular triglyceride level via increasing fatty acid uptake and fatty acid oxidation. PPARα was associated with the acetate-reduced intracellular fat content.

5.
Life Sci ; 235: 116863, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31513817

RESUMO

AIMS: To determine whether dimethyl fumarate (DMF) can protect against lipopolysaccharide (LPS) -induced myocardial injury. MAIN METHODS: H9c2 cells pretreated with or without DMF were stimulated with LPS. Cell viability and apoptosis were evaluated. Nrf2 and HO-1 expression were detected using Western blotting. Mitochondrial morphology, mitochondrial superoxide production were observed using confocal microscope. Mitochondrial respiration function was measured using Seahorse bioanalyzer. KEY FINDINGS: (1) The cell viability decreased, LDH release and apoptosis increased in LPS- challenged H9c2 cells. DMF pretreatment brought a higher cell viability, and a lower LDH leakage and apoptosis than those of LPS group (P < 0.01). (2) DMF pretreatment resulted in an increased Nrf2 and HO-1 expression, and enhanced nuclear Nrf2 level in LPS-challenged cells (P < 0.01). (3) Nrf2-siRNA could inhibit DMF-induced enhancement of HO-1 expression and cell viability, and partly abolish DMF-induced reduction of LDH leakage and apoptosis. (4) ERK1/2 inhibitor PD98059 could not only prevent the DMF-induced enhancement of nuclear Nrf2 and HO-1, but also inhibit DMF-induced increase in cell viability. (5) Compared with LPS-challenged cells, DMF pretreatment caused a lower production of mitochondrial superoxide and a higher mitochondrial membrane potential, which could be abolished by Nrf2-siRNA. (6) DMF could attenuate LPS-induced mitochondrial fragmentation and improve mitochondrial respiration function by enhancement of the oxygen consumption rate of basal respiration and ATP production in LPS-challenged cells (P < 0.01). SIGNIFICANCE: DMF protects cardiomyocytes against LPS-induced damage. ERK1/2-dependent activation of Nrf2/HO-1 pathway is responsible for DMF-induced cardioprotection via reduction of oxidative stress, improvement of mitochondrial morphology and energy metabolism.


Assuntos
Fumarato de Dimetilo/farmacologia , Mitocôndrias/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Trifosfato de Adenosina/biossíntese , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fumarato de Dimetilo/antagonistas & inibidores , Flavonoides/farmacologia , Heme Oxigenase-1/metabolismo , Humanos , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos/efeitos adversos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Miócitos Cardíacos/metabolismo , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Consumo de Oxigênio/efeitos dos fármacos , Substâncias Protetoras/farmacologia , RNA Interferente Pequeno/farmacologia , Superóxidos/metabolismo
6.
J Ethnopharmacol ; 245: 112149, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31401321

RESUMO

It has been widely reported that Xuefu Zhuyu decoction (XFZYD), a traditional Chinese medicine, is effective in the treatment of traumatic brain injury (TBI). However, the mechanism of the therapeutic process is still not fully understood. Metabolomic technique can be used to explore the mechanisms underlying the treatment of TBI with XFZYD. The purpose of this work was to investigate the metabolic characteristics of blood samples from rats with and without XFZYD treatment and the dynamic changes in metabolite profiles on days 1, 3, 7, 14 and 21 after injury (within the severe phase of TBI) based on untargeted UPLC-ESI-IT-TOF-MS analysis. Pattern recognition, clustering analysis and metabolic pathway analysis were used to analyse the metabolomic data of three groups (a sham-operated group, a TBI model, and an XFZYD-treated TBI model). The results showed that XFZYD reversed the abnormalities in the levels of small-molecule metabolites (such as L-acetylcarnitine, L-tryptophan, indoleacrylic acid, γ-aminobutyric acid, hypotaurine, LysoPC(18:1)(11Z), creatine, L-phenylalanine and L-leucine) in TBI rats through six metabolic pathways (including phenylalanine, tyrosine and tryptophan biosynthesis; phenylalanine metabolism; valine, leucine and isoleucine biosynthesis; taurine and hypotaurine metabolism; tryptophan metabolism; and alanine, aspartate and glutamate metabolism) involved in the therapy process. XFZYD regulated the metabolic disorders of endogenous markers by the possible mechanisms of neuroprotection, energy metabolism, inflammatory response and oxidative stress. This study revealed the holistic and dynamic metabolic changes caused by XFZYD in rats with TBI and provided important research methods and approaches for exploring the multiple metabolites and metabolic pathways involved in the therapeutic effect of XFZYD on TBI.

7.
Poult Sci ; 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31393590

RESUMO

The effects of maternal conjugated linoleic acid (CLA) on embryonic development and hepatic lipid metabolism were investigated in chick embryos. A total of 180 Arbor Acres female broiler breeders (36 wk old) were randomly divided into the following 3 dietary treatment groups: a basic diet (control), a basic diet containing 0.5% CLA (CLA1), and a basic diet containing 1.0% CLA (CLA2). The females were fed for 8 wk, and the eggs from each group were collected and hatched during the last 2 wk. The results showed that the addition of dietary CLA increased the broken egg rate and reduced the fertilization rate and the egg hatchability (P < 0.05). CLA enrichment decreased the polyunsaturated and monounsaturated fatty acids and increased the saturated fatty acids in the yolk sac (P < 0.05). The yolk sac weight, body weight, and body length had a linear decrease with CLA supplementation (P < 0.05). In the developing chick embryo (at E14) and newly hatched chick (D0), the serum triglyceride concentration decreased with maternal CLA supplementation and was accompanied by a reduction in subcutaneous adipose tissue deposition. In addition, maternal CLA supplementation mediated the hepatic lipid metabolism by decreasing the mRNA expression of sterol regulatory element-binding proteins-1c (SREBP-1c), fatty acid synthase and acetyl-CoA carboxylase, and increasing the mRNA expression of adenosine 5'-monophosphate-activated protein kinase α (AMPKα), peroxisome proliferator-activated receptors α (PPARα), liver fatty acid-binding protein, adipose triglyceride lipase and carnitine palmitoyltransferase in embryonic chick livers (P < 0.05). A drop in SREBP-1c protein expression and an increase in the protein expression of p-AMPKα and PPARα were also observed in the liver of chick embryo (P < 0.05). In conclusion, maternal CLA supplementation regulated the fatty acid composition in the yolk sac, and mediated embryonic chick development and hepatic lipometabolism, and these effects may be related to the AMPK pathway. These findings suggest the potential ability of maternal CLA supplementation to reduce fat deposition in chick embryos.

8.
J Cancer Res Ther ; 15(2): 350-357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964110

RESUMO

Background: We assessed the frequency of epigenetic lesions, including lymphoid-specific helicase (LSH), 5-hydroxymethylcytosine (5-hmC) and E2F1, and the possible correlations among molecular findings, phenotype, clinical features, and outcome. Methods: We investigated 181 paraffin-embedded B-cell lymphoma samples using immunohistochemistry and in situ hybridization. Results: The levels of Ki67, LSH, 5-hmC, and E2F1 were all increased in germinal center B-cell lymphomas when compared with those in normal lymph nodes, and LSH was highly expressed in diffuse large B-cell lymphomas (DLBCLs) and Burkitt lymphomas (BLs) that were positive for Epstein-Barr virus (EBV) infection, indicating that LSH is linked to EBV infection in DLBCL and BL. Interestingly, LSH was mainly localized in the germinal centers of lymph nodes whereas 5-hmC staining localized to areas surrounding the germinal centers. Conclusions: These findings indicate a critical role for LSH as a biomarker and therapeutic target in follicular germinal center B-cell lymphoma.


Assuntos
Montagem e Desmontagem da Cromatina , DNA Helicases/genética , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Centro Germinativo/patologia , Herpesvirus Humano 4 , Linfoma de Células B/etiologia , Linfoma de Células B/patologia , Biomarcadores , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica
9.
Nat Microbiol ; 4(5): 813-825, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30833724

RESUMO

Human immunodeficiency virus (HIV) actively modulates the protein stability of host cells to optimize viral replication. To systematically examine this modulation in HIV infection, we used isobaric tag-based mass spectrometry to quantify changes in the abundance of over 14,000 proteins during HIV-1 infection of human primary CD4+ T cells. We identified P-selectin glycoprotein ligand 1 (PSGL-1) as an HIV-1 restriction factor downregulated by HIV-1 Vpu, which binds to PSGL-1 and induces its ubiquitination and degradation through the ubiquitin ligase SCFß-TrCP2. PSGL-1 is induced by interferon-γ in activated CD4+ T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions. This infectivity block is antagonized by Vpu via PSGL-1 degradation. We further show that PSGL-1 knockdown can significantly abolish the anti-HIV activity of interferon-γ in primary CD4+ T cells. Our study identifies an HIV restriction factor and a key mediator of interferon-γ's anti-HIV activity.


Assuntos
Linfócitos T CD4-Positivos/virologia , Infecções por HIV/metabolismo , HIV-1/fisiologia , Interações Hospedeiro-Patógeno , Glicoproteínas de Membrana/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Infecções por HIV/genética , Infecções por HIV/fisiopatologia , Infecções por HIV/virologia , HIV-1/genética , Proteínas do Vírus da Imunodeficiência Humana/genética , Proteínas do Vírus da Imunodeficiência Humana/metabolismo , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Glicoproteínas de Membrana/genética , Proteólise , Proteômica , Proteínas Ligases SKP Culina F-Box/genética , Proteínas Ligases SKP Culina F-Box/metabolismo , Ubiquitinação , Proteínas Virais Reguladoras e Acessórias/genética , Proteínas Virais Reguladoras e Acessórias/metabolismo
10.
Metallomics ; 11(3): 565-575, 2019 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-30761393

RESUMO

Myocardial ischemia leads to copper efflux from the heart. The ischemic tissue with a low copper content fails to take up copper from the circulation even under the conditions of serum copper elevation. Cardiac copper repletion thus requires other available forms of this element than those currently known to bind to copper transport proteins. The copper complex of triethylenetetramine (TETA) is a metabolite of TETA, which has the potential to increase cardiac copper content in vivo. In the present study, we synthesized Cu(ii)-TETA, analyzed its crystal structure, and demonstrated the role of this compound in facilitating copper accumulation in primary cultures of neonatal rat cardiomyocytes. The Cu(ii)-TETA compound formed a square pyramidal chloride salt [Cu(TETA)Cl]Cl structure, which dissociates from chloride in aqueous solution to yield the four-coordinate dication Cu(ii)-TETA. Cu(ii)-TETA was accumulated as an intact compound in cardiomyocytes. Analysis from time-dependent copper accumulation in cardiomyocytes defined a different dynamic process in copper uptake between Cu(ii)-TETA and CuCl2 exposure. An additive copper accumulation in cardiomyocytes was found when the cells were exposed to both CuCl2 and Cu(ii)-TETA. Gene silencing of copper transport 1 (CTR1) did not affect cross-membrane transportation of Cu(ii)-TETA, but inhibited copper cellular accumulation from CuCl2. Furthermore, the uptake of Cu(ii)-TETA by cardiomyocytes was ATP-dependent. It is thus concluded that the formation of Cu(ii)-TETA facilitates copper accumulation in cardiomyocytes through an active CTR1-independent transportation process.

11.
Chemosphere ; 220: 259-265, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30590292

RESUMO

Horizontal subsurface flow constructed wetlands (CWs) planted with Phragmites australis were set up to analyze the effect of external ferrous iron (Fe2+) addition on chemical oxygen demand (COD) and nitrogen removal. The results showed that external Fe2+ addition has no significant effect on COD removal, while the COD removal efficiencies in CWs with Fe2+ addition were slightly lower than those in CWs without Fe2+ addition, since Fe2+ as an electron donor for denitrification may decrease the consumption of organic carbon. However, external Fe2+ addition significantly enhanced the nitrogen removal capability of the CWs. With an increase in external Fe2+ concentration, the removal efficiencies for total nitrogen (TN), nitrate nitrogen (NO3N), and ammonium nitrogen (NH4N) all increased. The removal efficiencies for TN and NH4N were greatest for an influent Fe2+ concentration of 50 mg L-1, while the greatest removal efficiencies for NO3N were observed at an influent Fe2+ concentration of 150 mg L-1. With increasing hydraulic retention time (HRT), the COD and NO3N removal efficiencies in the CWs with external Fe2+ addition increase sharply and then became stable, while the removal efficiency for TN exhibited a continuous increase. The removal efficiency for NH4N was greatest at an HRT of 5 d-7 d with Fe2+ addition. The change in pH with increasing HRT indicated that external Fe2+ addition did not significantly affect the pH value of the effluent water, but that the wetland systems caused an increase in effluent pH. Fe2+ addition remarkably reduced the oxygen-reduction potential of both the influent and effluent water, which was beneficial to denitrification of microorganisms.


Assuntos
Análise da Demanda Biológica de Oxigênio , Desnitrificação , Ferro/farmacologia , Nitrogênio/isolamento & purificação , Poaceae/efeitos dos fármacos , Eliminação de Resíduos Líquidos/métodos , Áreas Alagadas , Nitrogênio/química
12.
Life Sci ; 210: 47-54, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30170072

RESUMO

AIMS: To determine whether linagliptin, a dipeptidyl peptidase 4 inhibitor, can promote the recovery of cardiac function after hypothermic preservation. MAIN METHODS: Rat hearts were preserved in cold Celsior solution with or without linagliptin for 9 h. Cardiac function was evaluated at 60 min of reperfusion after hypothermic preservation. Cardiac mitochondrial morphology was observed using transmission electron microscope. The expression of dynamin-related protein 1 (Drp1), NADPH oxidase 2 (NOX2), calmodulin-dependent protein kinase II (CaMKII) were detected using Western blot. KEY FINDINGS: Compared with Celsior group, supplement of Celsior solution with linagliptin (0.25-0.75 nM) could significantly prevent hypothermic preservation-induced cardiac dysfunction. The expression of NOX2 protein, ROS level and MDA content in cardium were increased after hypothermic preservation, which was inhibited by linagliptin. Although the mitofusin1, 2, optic atrophy type 1, and total Drp1 expression in myocardium did not change, the level of p-Drp1 S616 and mitochondrial Drp1 were enhanced after hypothermic preservation. Linagliptin supplement could inhibit the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein, and mitigate the mitochondrial fragmentation. Level of p-CaMKII protein enhanced after hypothermic preservation, which could be prevented by linagliptin or a NOX2 inhibitor Phox-I2. Both Phox-I2 and a CaMKII inhibitor KN-93 could reduce the hypothermic preservation-induced increase in p-Drp1 S616 and mitochondrial Drp1 protein. SIGNIFICANCE: Supplement Celsior solution with linagliptin could improve cardiac function recovery in 9-h hypothermic preserved rat hearts. The cardioprotective effect of linagliptin might be due to the inhibition of Drp1 phosphorylation and mitochondrial translocation by preventing NOX2-mediated CaMKII activation.


Assuntos
Criopreservação/métodos , Coração/fisiologia , Linagliptina/farmacologia , Miocárdio/metabolismo , Soluções para Preservação de Órgãos/farmacologia , Preservação de Órgãos/métodos , Recuperação de Função Fisiológica , Animais , Inibidores da Dipeptidil Peptidase IV/farmacologia , Coração/efeitos dos fármacos , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Ratos , Ratos Sprague-Dawley
13.
J Cancer Res Ther ; 14(4): 838-843, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29970662

RESUMO

Objective: The objective of this study is to elucidate the regulation of the DPC4 gene by miR-190 in colorectal cancer (CRC) cells. The present study was undertaken to determine whether the DPC4 gene is a target gene of miRNA-190, identify target motifs and to elucidate the mechanism of regulation of DPC4 by miRNA-190. Materials and Methods: MiR-190 and DPC4 expression were measured in five different CRC cell lines by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. The regulation of DPC4 by miR-190 was evaluated by qRT-PCR, Western blotting, and luciferase reporter assays in the human CRC cell line HT-29 after treatment with miR-190 mimics and inhibitors. Results: The DPC4 mRNA, miR-, and DPC4 protein expression levels were highest in LS174T cells while lowest in SW480 and SW620 cells. The DPC4/miR-190 ratio in the HT-29 cancer cell line was the largest. MiR-190 expression increased dramatically after treatment with miR-190 mimics and decreased significantly after treatment with miR-190 inhibitors. DPC4 protein expression decreased in the miR-190 mimics transfection group when compared to the negative control (N.C.) group and increased in the miR-190 inhibitor groups when compared to the inhibitor plus N.C. group. MiR-190 inhibits the relative luciferase activity of psiCHECK-2™ vector-3'UTR compared to the N.C. group, while miR-190 had no obvious effect on the relative luciferase activity of the psiCHECK-2™ vector-3'UTRmut and psiCHECK-2™ vector transfected cells. Conclusions: The DPC4 gene might be the target gene of miR-190, which may negatively regulate the DPC4 gene in human CRC cells by translational suppression rather than mRNA degradation.


Assuntos
Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , Proteína Smad4/genética , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Genes Reporter , Células HT29 , Humanos , Processamento Pós-Transcricional do RNA
14.
Sci Total Environ ; 635: 1360-1366, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29710589

RESUMO

Horizontal subsurface constructed wetlands (HSSF-CWs) planted with Phragmites australis were established to examine the effect of influent nitrogen loads on the removal efficiencies of nitrogen and chemical oxygen demand (COD) during different plant growth periods of plants. Under low influent nitrogen loads, most of the dissolved oxygen was consumed during the oxidation of organic matter in the wetland systems, and a dissimilatory nitrate reduction to ammonium (DNRA) may have occurred in HSSF-CWs when excessive amounts of organic matter were present, which limited the nitrification of ammonium nitrogen (NH4-N) and hindered the NH4-N removal. An increase in the influent nitrogen loads resulted in an enhancement of the removal efficiencies of NH4-N, nitrate nitrogen (NO3-N) and total nitrogen (TN) during the same growth period, except for NO3-N under the highest influent nitrogen loads, whereas fluctuations occurred for the COD removal efficiency. Compared with the rapid growth period, the removal efficiency of NH4-N, NO3-N and TN increased during the mature period; however, the COD removal efficiency decreased. The change of COD: N (COD:TN in wastewater) ratios with retention times indicated the sufficiency or deficiency of organic matter as an electron donor in the wetland systems. The changes in the pH value and oxidation-reduction potential (ORP) indirectly demonstrated that many factors affected the effluent pH value and ORP, such as retention time, influent loads, plants and wetland substrate, and microorganisms. In this study, the changes of ORP also illustrated that the dissolved oxygen concentrations decreased with increasing retention time in the HSSF-CWs; however, no significant increase in the ORP was observed during the two growth periods.

15.
Eur J Med Chem ; 149: 30-44, 2018 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-29494843

RESUMO

The important roles of the CXCL12/CXCR4 axis in numerous pathogenic pathways involving HIV infection and cancer metastasis make the CXCR4 receptor an attractive target for the development of therapeutic agents. Through scaffold hybridization of a few known CXCR4 antagonists, a series of novel aminopyrimidine derivatives was developed. Compound 3 from this new scaffold demonstrates excellent binding affinity with CXCR4 receptor (IC50 = 54 nM) and inhibits CXCL12 induced cytosolic calcium increase (IC50 = 2.3 nM). Furthermore, compound 3 possesses good physicochemical properties (MW 353, clogP 2.0, PSA 48, pKa 6.7) and exhibits minimal hERG and CYP isozyme (e.g. 3A4, 2D6) inhibition. Collectively, these results strongly support further optimization of this novel scaffold to develop better CXCR4 antagonists.


Assuntos
Desenho de Drogas , Pirimidinas/química , Receptores CXCR4/antagonistas & inibidores , Cálcio/metabolismo , Quimiocina CXCL12/fisiologia , Humanos , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/farmacologia , Relação Estrutura-Atividade
16.
J Cancer Res Ther ; 13(5): 807-812, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29237908

RESUMO

OBJECTIVE: The objective of this study is to investigate the histogenesis of lymphoepithelial carcinoma (LEC) and its relationship with Epstein-Barr virus (EBV). MATERIALS AND METHODS: The expression of EBV was detected using in situ hybridization, and the CK5/6, p63, and p40 expression levels were detected using immunohistochemistry in 45 paraffin-embedded tissues from LEC. RESULTS: In 45 paraffin-embedded LEC tissues from 10 different samples, the positive CK5/6 signals were located in the cell membrane. The positive signals for p63 and p40 were located in the cell nucleus. In all LEC cases, the positive rates of CK5/6, p63, and p40 were 93.3% (42/45), 95.6% (43/45), and 93.3% (42/45), respectively. The positive EBV-encoded RNA (EBER) signals were located in the cell nucleus. In the 45 LEC cases, the expression of EBER was strongly positive with a positive rate of 100% (45/45). CONCLUSIONS: LEC is closely related to EBV, and EBV plays an important role in the development of LEC. LEC showed positive squamous cell markers, indicating that the samples contain squamous cell carcinoma (SQCC). LEC is EBV (+) with nonkeratinizing SQCC, and this name better reflects the nature of this disease.


Assuntos
Carcinoma de Células Escamosas/virologia , Células Epiteliais/virologia , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/isolamento & purificação , RNA Viral/isolamento & purificação , Adulto , Biomarcadores/metabolismo , Carcinoma de Células Escamosas/patologia , Membrana Celular/metabolismo , Núcleo Celular/metabolismo , China , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , RNA Viral/metabolismo
17.
Oncotarget ; 8(44): 77009-77019, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100365

RESUMO

Objective: To discuss the clinical value of immunoglobulin gene rearrangements in the diagnosis of B-cell lymphoma. Methods: A total of 209 cases of B-cell lymphomas and 35 cases of reactive lymphoid hyperplasia were selected for DNA extraction and PCR amplification using the BIOMED-2 primer system. Gel electrophoresis of heteroduplexes was used to analyze immunoglobulin gene rearrangements. Results: A total of 209 cases of B-cell lymphoma, including 69 extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue, 63 diffuse large B-cell lymphomas, 39 follicular lymphomas, 15 small lymphocytic lymphomas, 6 plasmacytomas, 6 mantle cell lymphomas, 7 nodal marginal zone B-cell lymphomas, and 4 lymphoplasmacytoid lymphomas, were examined. Immunoglobulin gene rearrangements were found in all 209 cases, with 93 IGHA, 122 IGHB, 98 IGHC, 167 IGK, 100 IGL, 167 IGHA/B/C, 204 IGH/IGK, 209 IGH/IGK/IGL, 129 IGH+IGK, 81 IGH+IGL, 83 IGK+IGL and 68 IGH+IGK+IGL gene rearrangements. Immunoglobulin gene rearrangements were not found in the 35 cases of reactive lymphoid hyperplasia. IGH and IGK gene rearrangements were mainly found in mantle cell lymphomas, small lymphocytic lymphomas, extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue and diffuse large B-cell lymphomas. The IGH gene rearrangement was mainly found in lymphoplasmacytoid lymphomas and follicular lymphomas. IGK and IGL gene rearrangements were mainly found in plasmocytoma, and the IGK gene rearrangement was mainly found in nodal marginal zone B-cell lymphomas. Conclusions: The BIOMED-2 standardized immunoglobulin gene rearrangement detection system is an important tool in B-cell lymphoma diagnosis. Analysis of IGH, IGK and IGL gene rearrangements is valuable in confirming the classification of B-cell NHL.

18.
Theranostics ; 7(1): 132-143, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28042322

RESUMO

The signaling pathway-based stratification in chromatin modification could predict clinical outcome more reliably than morphology-alone-based classification schemes in gliomas. Here we reported a role of the chromatin-remodeling factor lymphoid-specific helicase (LSH) in gliomas. Among astrocytomas of grade I to III and glioblastoma of grade IV, LSH were almost completely expressed in all cases, and strongly correlated with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Ectopic expression of LSH promoted tumor formation. Up-regulation of transcription factor E2F1 in astrocytomas and glioblastoma was associated with the progression of gliomas and correlated with LSH expression. Chromatin immunoprecipitation (ChIP) analysis showed transcription factor E2F1 were recruited to the promoter region of LSH, and depletion of E2F1 decreased LSH expression and cell growth. Moreover, glycogen synthase kinase-3ß (GSK-3ß), an intact complex of E2F1, were also highly expressed in astrocytomas and linked with astrocytomas progression and poor prognosis of patients with astrocytomas and glioblastoma. Inhibition of GSK3ß increased the enrichment of E2F1 to the LSH promoter, in turn, increased LSH expression. Lipoprotein receptor-related protein 6 (LRP6), an upstream regulator of GSK3ß signaling pathway, was highly expressed in gliomas. Knockdown of LRP6 decreased LSH expression through decrease of recruitment of E2F1 to the LSH promoter leading to inhibition of cell growth. Taken together, this study reveals evidence demonstrating a mechanism by which upregulated promoted gliomas. A mechanistic link between LSH expression and activation of the LPR6/ GSK3ß/E2F1 axis in gliomas illustrates a novel role of LSH in malignant astrocytomas and glioblastoma.


Assuntos
Astrocitoma/fisiopatologia , Montagem e Desmontagem da Cromatina , DNA Helicases/metabolismo , Fator de Transcrição E2F1/metabolismo , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Humanos , Sobrevida
19.
FEBS J ; 284(1): 97-113, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27981746

RESUMO

HIV-1-infected macrophages are a key contributor to the formation of a viral reservoir and new treatment strategies focus on eliminating this pool of virus. Galectin-3 is a potent apoptosis-inducing protein that regulates diverse cellular activities. In the present study, we investigated whether galectin-3 could induce cell death in HIV-1-infected macrophages using HIV-1-infected THP1 monocytes (THP1-MNs) and THP1-derived macrophages (THP1-MΦs) as in vitro cellular models. We found that THP1-MΦs were more resistant than the THP1-MNs to HIV-1 infection-induced death, and that HIV-1 infection of the THP1-MΦs increased expression of the anti-apoptotic proteins Mcl-1, Bcl-2 and Bcl-xL. Additionally, galectin-3 but not FasL, tumor necrosis factor (TNF)-related apoptosis-inducing ligand or TNF-α, could induce cell death in HIV-1-infected THP1-MΦs. A similar result was shown for primary human monocyte-derived macrophages. Galectin-3-induced cell death was also significantly increased in macrophages obtained from SIVmac251-infected macaques compared to that of macrophages from healthy macaques. Furthermore, galectin-3-induced cell death in HIV-1-infected THP1-MΦs was caspase independent. Interestingly, endonuclease G (Endo G) was increased in the nucleus and decreased in the cytoplasm of galectin-3-treated cells; thus, galectin-3-induced cell death in HIV-1-infected THP1-MΦs is most likely related to the translocation of Endo G from the cytoplasm to the nucleus. These findings suggest that galectin-3 may potentially aid in the eradication of HIV-1/SIV-infected macrophages.


Assuntos
Endodesoxirribonucleases/genética , Galectina 3/farmacologia , HIV-1/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Transporte Ativo do Núcleo Celular/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citoplasma/efeitos dos fármacos , Citoplasma/metabolismo , Endodesoxirribonucleases/metabolismo , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Galectina 3/genética , Galectina 3/metabolismo , Regulação da Expressão Gênica , HIV-1/crescimento & desenvolvimento , Humanos , Macaca , Macrófagos/patologia , Macrófagos/virologia , Monócitos/patologia , Monócitos/virologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Transporte Proteico/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Vírus da Imunodeficiência Símia/crescimento & desenvolvimento , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/farmacologia , Fator de Necrose Tumoral alfa/farmacologia , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
20.
J Sep Sci ; 39(17): 3457-68, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27384131

RESUMO

Xue Fu Zhu Yu Decoction, a famous formula that has been used for treating many blood stasis-caused diseases for many centuries, comprises 11 kinds of traditional Chinese medicines. A convenient, efficient, and rapid analytical method was developed to simultaneously determine the major compounds in this decoction. An ultra-high performance liquid chromatography with hybrid ion trap time-of-flight mass spectrometry method was used to rapidly separate and detect the major constituents of the decoction. Using this technique, we identified or tentatively identified 34 compounds, including 21 flavonoids, 5 terpenoids, 3 organic acids, 2 lactones, 1 alkaloid, 1 amino acid, and 1 cyanogenic glycoside. The MS analysis of these constituents was described in detail. Findings may contribute to future metabolic and pharmacokinetic studies of this medicine.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/química , Espectrometria de Massas/métodos , Plantas Medicinais/química , Medicina Tradicional Chinesa
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