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1.
Neuroimage ; 297: 120753, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-39053636

RESUMO

For patients with disorders of consciousness (DoC), accurate assessment of residual consciousness levels and cognitive abilities is critical for developing appropriate rehabilitation interventions. In this study, we investigated the potential of electrooculography (EOG) in assessing language processing abilities and consciousness levels. Patients' EOG data and related electrophysiological data were analysed before and after explicit language learning. The results showed distinct differences in vocabulary learning patterns among patients with varying levels of consciousness. While minimally conscious patients showed significant neural tracking of artificial words and notable learning effects similar to those observed in healthy controls, whereas patients with unresponsive wakefulness syndrome did not show such effects. Correlation analysis further indicated that EOG detected vocabulary learning effects with comparable validity to electroencephalography, reinforcing the credibility of EOG indicator as a diagnostic tool. Critically, EOG also revealed significant correlations between individual patients' linguistic learning performance and their Oromotor/verbal function as assessed through behavioural scales. In conclusion, this study explored the differences in language processing abilities among patients with varying consciousness levels. By demonstrating the utility of EOG in evaluating consciousness and detecting vocabulary learning effects, as well as its potential to guide personalised rehabilitation, our findings indicate that EOG indicators show promise as a rapid, accurate and effective additional tool for diagnosing and managing patients with DoC.


Assuntos
Transtornos da Consciência , Eletroculografia , Humanos , Masculino , Feminino , Adulto , Transtornos da Consciência/fisiopatologia , Transtornos da Consciência/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem , Aprendizagem/fisiologia , Eletroencefalografia/métodos , Idoso
2.
J Hepatol ; 80(5): 792-804, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38331327

RESUMO

BACKGROUND & AIMS: Natural killer (NK) cell-based anti-hepatocellular carcinoma (HCC) therapy is an increasingly attractive approach that warrants further study. Siglec-9 interacts with its ligand (Siglec-9L) and restrains NK cell functions, suggesting it is a potential therapeutic target. However, in situ Siglec-9/Siglec-9L interactions in HCC have not been reported, and a relevant interventional strategy is lacking. Herein, we aim to illustrate Siglec-9/Siglec-9L-mediated cell sociology and identify small-molecule inhibitors targeting Siglec-9 that could improve the efficacy of NK cell-based immunotherapy for HCC. METHODS: Multiplexed immunofluorescence staining was performed to analyze the expression pattern of Siglec-7, -9 and their ligands in HCC tissues. Then we conducted docking-based virtual screening combined with bio-layer interferometry assays to identify a potent small-molecule Siglec-9 inhibitor. The therapeutic potential was further evaluated in vitro and in hepatoma-bearing NCG mice. RESULTS: Siglec-9 expression, rather than Siglec-7, was markedly upregulated on tumor-infiltrating NK cells, which correlated significantly with reduced survival of patients with HCC. Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival, further suggesting that Siglec-9/Siglec-9L interactions are a potential therapeutic target in HCC. In addition, we identified a small-molecule Siglec-9 inhibitor MTX-3937 which inhibited phosphorylation of Siglec-9 and downstream SHP1 and SHP2. Accordingly, MTX-3937 led to considerable improvement in NK cell function. Notably, MTX-3937 enhanced cytotoxicity of both human peripheral and tumor-infiltrating NK cells. Furthermore, transfer of MTX-3937-treated NK92 cells greatly suppressed the growth of hepatoma xenografts in NCG mice. CONCLUSIONS: Our study provides the rationale for HCC treatment by targeting Siglec-9 on NK cells and identifies a promising small-molecule inhibitor against Siglec-9 that enhances NK cell-mediated HCC surveillance. IMPACT AND IMPLICATIONS: Herein, we found that Siglec-9 expression is markedly upregulated on tumor-infiltrating natural killer (TINK) cells and correlates with reduced survival in patients with hepatocellular carcinoma (HCC). Moreover, the number of Siglec-9L+ cells neighboring Siglec-9+ NK cells was increased in HCC tissues and was also associated with tumor recurrence and reduced survival. More importantly, we identified a small-molecule inhibitor targeting Siglec-9 that augments NK cell functions, revealing a novel immunotherapy strategy for liver cancer that warrants further clinical investigation.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/metabolismo , Células Matadoras Naturais/patologia , Imunoterapia , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo , Ligantes , Prognóstico
3.
Cancer Immunol Immunother ; 72(12): 4355-4365, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37907645

RESUMO

BACKGROUND: Whether patients with advanced non-small cell lung cancer (NSCLC) should choose an immune-combination therapy regimen after EGFR-tyrosine kinase inhibitors (EGFR-TKIs) resistance is currently unclear. METHODS: We evaluated 118 NSCLC patients treated by immune checkpoint inhibitors (ICIs) + chemotherapy (I + C), ICIs + chemotherapy + antiangiogenic therapy (I + C + A), chemotherapy + antiangiogenic therapy (C + A) after inefficacy of EGFR-TKIs. We assessed the objective remission rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of these treatments. RESULTS: The ORR was 26.1% vs 38.2% vs 16.3% in the three groups (P = 0.093). The divergence in DCR was also statistically significant (65.2% vs 85.3% vs 74.4%, P = 0.209). The median PFS was no statistically significant difference in PFS (3.09 vs 6.31 vs 5.91 months, P = 0.809), but the Kaplan-Meier survival curve of 12-month-PFS indicated an apparent survival advantage in the I + C + A group (P = 0.001). In addition, the I + C/I + C + A group showed higher median PFS than the C + A group in patients with brain metastases (median PFS, 6.44 vs 4.21 months, P = 0.022). The divergence in ORR of patients in the brain group was also statistically significant (P = 0.045). The I + C + A group showed superior efficacy in patients with liver metastases (median PFS, 0.95 vs 6.44 vs 3.48 months, P < 0.0001). The Cox proportional hazard modeling analysis suggested that the age, brain metastases, and liver metastases were all connected with the prognosis. CONCLUSIONS: This study suggests that advanced NSCLC patients after resistance to EGFR-TKIs may achieve better outcomes from triple therapy. Patients with brain metastases favor ICIs-related combination therapies and patients with liver metastases prefer I + C + A therapy.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Hepáticas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Estudos Retrospectivos , Inibidores de Proteínas Quinases/farmacologia , Neoplasias Encefálicas/secundário , Receptores ErbB/genética , Neoplasias Hepáticas/tratamento farmacológico , Mutação
4.
Int J Mol Sci ; 19(7)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29966265

RESUMO

Here, we investigated the effects of selenium (Se) applications on two strawberry varieties, Akihime and Benihoppe, under chilling stress and recovery conditions. Changes in photosynthetic parameters, antioxidant enzyme activities, ascorbate (AsA)-glutathione (GSH) cycle-related enzyme activities, and low-molecular-mass antioxidant contents were determined. Foliar spraying with Se alleviated the decline in the net photosynthetic rate and chlorophyll content and increased the malondialdehyde and hydrogen peroxide contents of strawberry seedlings’ leaves under chilling stress. As the time under chilling stress increased, the stomatal conductance decreased and intercellular CO2 concentration increased, suggesting that nonstomatal factors had major limiting effects on the net photosynthetic rate's decrease. Se applications significantly alleviated the adverse impacts of chilling stress on changes in stomatal conductance and intercellular CO2 concentration. Se, especially at lower concentrations, significantly increased superoxide dismutase, catalase, and peroxide enzyme activities during chilling stress. Approximately 5 mg·L−1 of sodium selenite solution had the greatest stress-alleviating effects. Among the AsA-GSH cycle-related enzymes, ascorbate peroxidase, glutathione reductase, dehydroascorbate reductase, and monodehydroascorbate reductase (MDHAR) treatments, coupled with an appropriate dose of Se, significantly enhanced ascorbate peroxidase and MDHAR activities, which suggested that Se applications played important roles in strawberry leaves by affecting AsA-GSH cycle-related defenses against the oxidative damage caused by chilling stress. Furthermore, MDHAR was the key enzyme required to maintain the balance between AsA consumption and regeneration that may assist in protecting strawberry seedlings in a low-temperature environment.


Assuntos
Selênio/farmacologia , Catalase/metabolismo , Temperatura Baixa , Glutationa/metabolismo , NADH NADPH Oxirredutases/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/metabolismo , Plântula/efeitos dos fármacos , Plântula/metabolismo , Superóxido Dismutase/metabolismo
5.
Immunogenetics ; 68(10): 765-781, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27516207

RESUMO

The major histocompatibility complex (MHC) region contains many genes that are key regulators of both innate and adaptive immunity including the polymorphic MHCI and MHCII genes. Consequently, the characterisation of the repertoire of MHC genes is critical to understanding the variation that determines the nature of immune responses. Our current knowledge of the bovine MHCI repertoire is limited with only the Holstein-Friesian breed having been studied in any depth. Traditional methods of MHCI genotyping are of low resolution and laborious and this has been a major impediment to a more comprehensive analysis of the MHCI repertoire of other cattle breeds. Next-generation sequencing (NGS) technologies have been used to enable high throughput and much higher resolution MHCI typing in a number of species. In this study we have developed a MiSeq platform approach and requisite bioinformatics pipeline to facilitate typing of bovine MHCI repertoires. The method was validated initially on a cohort of Holstein-Friesian animals and then demonstrated to enable characterisation of MHCI repertoires in African cattle breeds, for which there was limited or no available data. During the course of these studies we identified >140 novel classical MHCI genes and defined 62 novel MHCI haplotypes, dramatically expanding the known bovine MHCI repertoire.


Assuntos
Bovinos/genética , Deriva Genética , Variação Genética/genética , Genética Populacional , Haplótipos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Antígenos de Histocompatibilidade Classe I/genética , Animais , Biologia Computacional , Genótipo , Reação em Cadeia da Polimerase
6.
J Clin Microbiol ; 54(6): 1557-1565, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27053669

RESUMO

Contagious bovine pleuropneumonia (CBPP) is a severe respiratory disease that is widespread in sub-Saharan Africa. It is caused by Mycoplasma mycoides subsp. mycoides, a bacterium belonging to the Mycoplasma mycoides cluster. In the absence of an efficient CBPP vaccine, improved and easy-to-use diagnostic assays for recurrent testing combined with isolation and treatment of positive animals represent an option for CBPP control in Africa. Here we describe the comprehensive screening of 17 immunogenic Mycoplasma mycoides subsp. mycoides proteins using well-characterized bovine sera for the development of a novel cocktail enzyme-linked immunosorbent assay (ELISA) for laboratory use. Two recombinant Mycoplasma immunogens, MSC_0136 and MSC_0636, were used to set up a standardized cocktail ELISA protocol. According to the results from more than 100 serum samples tested, the sensitivity and specificity of the novel cocktail ELISA were 85.6% and 96.4%, respectively, with an overall diagnostic accuracy comparable to that of the Office International des Epizooties (OIE)-prescribed serological assays. In addition, we provide a proof of principle for a field-applicable, easy-to-use commercially produced prototype lateral-flow test for rapid (<30-min) diagnosis of CBPP.


Assuntos
Anticorpos Antibacterianos/sangue , Doenças dos Bovinos/diagnóstico , Cromatografia de Afinidade/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Mycoplasma mycoides/imunologia , Pleuropneumonia Contagiosa/diagnóstico , África Subsaariana , Animais , Bovinos , Sensibilidade e Especificidade , Fatores de Tempo
7.
J Clin Microbiol ; 53(9): 2810-5, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26085615

RESUMO

Contagious caprine pleuropneumonia (CCPP) is a highly contagious disease caused by Mycoplasma capricolum subsp. capripneumoniae that affects goats in Africa and Asia. Current available methods for the diagnosis of Mycoplasma infection, including cultivation, serological assays, and PCR, are time-consuming and require fully equipped stationary laboratories, which make them incompatible with testing in the resource-poor settings that are most relevant to this disease. We report a rapid, specific, and sensitive assay employing isothermal DNA amplification using recombinase polymerase amplification (RPA) for the detection of M. capricolum subsp. capripneumoniae. We developed the assay using a specific target sequence in M. capricolum subsp. capripneumoniae, as found in the genome sequence of the field strain ILRI181 and the type strain F38 and that was further evidenced in 10 field strains from different geographical regions. Detection limits corresponding to 5 × 10(3) and 5 × 10(4) cells/ml were obtained using genomic DNA and bacterial culture from M. capricolum subsp. capripneumoniae strain ILRI181, while no amplification was obtained from 71 related Mycoplasma isolates or from the Acholeplasma or the Pasteurella isolates, demonstrating a high degree of specificity. The assay produces a fluorescent signal within 15 to 20 min and worked well using pleural fluid obtained directly from CCPP-positive animals without prior DNA extraction. We demonstrate that the diagnosis of CCPP can be achieved, with a short sample preparation time and a simple read-out device that can be powered by a car battery, in <45 min in a simulated field setting.


Assuntos
Técnicas de Diagnóstico Molecular/métodos , Mycoplasma capricolum/isolamento & purificação , Técnicas de Amplificação de Ácido Nucleico/métodos , Pleuropneumonia Contagiosa/diagnóstico , Medicina Veterinária/métodos , Animais , Cabras , Sensibilidade e Especificidade , Fatores de Tempo
8.
Proc Natl Acad Sci U S A ; 108(17): 7058-63, 2011 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-21482757

RESUMO

Lung morphogenesis is a well orchestrated, tightly regulated process through several molecular pathways, including TGF-ß/bone morphogenetic protein (BMP) signaling. Alteration of these signaling pathways leads to lung malformation. We investigated the role of Follistatin-like 1 (Fstl1), a secreted follistatin-module-containing glycoprotein, in lung development. Deletion of Fstl1 in mice led to postnatal lethality as a result of respiratory failure. Analysis of the mutant phenotype showed that Fstl1 is essential for tracheal cartilage formation and alveolar maturation. Deletion of the Fstl1 gene resulted in malformed tracheal rings manifested as discontinued rings and reduced ring number. Fstl1-deficient mice displayed septal hypercellularity and end-expiratory atelectasis, which were associated with impaired differentiation of distal alveolar epithelial cells and insufficient production of mature surfactant proteins. Mechanistically, Fstl1 interacted directly with BMP4, negatively regulated BMP4/Smad1/5/8 signaling, and inhibited BMP4-induced surfactant gene expression. Reducing BMP signaling activity by Noggin rescued pulmonary atelectasis of Fstl1-deficient mice. Therefore, we provide in vivo and in vitro evidence to demonstrate that Fstl1 modulates lung development and alveolar maturation, in part, through BMP4 signaling.


Assuntos
Proteína Morfogenética Óssea 4/antagonistas & inibidores , Proteína Morfogenética Óssea 4/metabolismo , Proteínas Relacionadas à Folistatina/metabolismo , Alvéolos Pulmonares/embriologia , Transdução de Sinais/fisiologia , Animais , Proteína Morfogenética Óssea 4/genética , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cartilagem/citologia , Cartilagem/embriologia , Linhagem Celular Tumoral , Proteínas Relacionadas à Folistatina/genética , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Humanos , Camundongos , Camundongos Knockout , Alvéolos Pulmonares/citologia , Surfactantes Pulmonares/metabolismo , Proteínas Smad/genética , Proteínas Smad/metabolismo , Traqueia/citologia , Traqueia/embriologia
9.
Brain Commun ; 6(2): fcae058, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38444912

RESUMO

The hub-and-spoke theory of semantic representation fractionates the neural underpinning of semantic knowledge into two essential components: the sensorimotor modality-specific regions and a crucially important semantic hub region. Our previous study in patients with semantic dementia has found that the hub region is located in the left fusiform gyrus. However, because this region is located within the brain damage in patients with semantic dementia, it is not clear whether the semantic deficit is caused by structural damage to the hub region itself or by its disconnection from other brain regions. Stroke patients do not have any damage to the left fusiform gyrus, but exhibit amodal and modality-specific deficits in semantic processing. Therefore, in this study, we validated the semantic hub region from a brain network perspective in 79 stroke patients and explored the white matter connections associated with it. First, we collected data of diffusion-weighted imaging and behavioural performance on general semantic tasks and modality-specific semantic tasks (assessing object knowledge on form, colour, motion, sound, manipulation and function). We then used correlation and regression analyses to examine the association between the nodal degree values of brain regions in the whole-brain structural network and general semantic performance in the stroke patients. The results revealed that the connectivity of the left fusiform gyrus significantly predicted general semantic performance, indicating that this region is the semantic hub. To identify the semantic-relevant connections of the semantic hub, we then correlated the white matter integrity values of each tract connected to the left fusiform gyrus separately with performance on general and modality-specific semantic processing. We found that the hub region accomplished general semantic processing through white matter connections with the left superior temporal pole, middle temporal gyrus, inferior temporal gyrus and hippocampus. The connectivity between the hub region and the left hippocampus, superior temporal pole, middle temporal gyrus, inferior temporal gyrus and parahippocampal gyrus was differentially involved in object form, colour, motion, sound, manipulation and function processing. After statistically removing the effects of potential confounding variables (i.e. whole-brain lesion volume, lesion volume of regions of interest and performance on non-semantic control tasks), the observed effects remained significant. Together, our findings support the role of the left fusiform gyrus as a semantic hub region in stroke patients and reveal its crucial connectivity in the network. This study provides new insights and evidence for the neuroanatomical organization of semantic memory in the human brain.

10.
Int J Anal Chem ; 2023: 2096521, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37881366

RESUMO

Pharmaceutical companies and regulatory agencies have more and more concerns for impurities in pharmaceuticals and their toxicity. In this work, heart-cutting two-dimensional ultrahigh-performance liquid chromatography (2D-UHPLC) in combination with high-resolution mass spectrometry (HRMS) was used, setting HRMS as positive mode of electrospray ionization to identify five impurities in pioglitazone hydrochloride preparations. With the heart-cutting 2D-UHPLC and online desalting technique, the structures of five impurities were deduced in an analysis of MSn data. And three of them, Impurity-2, Impurity-3, and Impurity-5, have never been reported before. The fragmentation patterns of five impurities were proposed on a basis of accurate mass and fragment ions in this study. Since the toxicity of impurities is relevant to their structures, toxicology of all five impurities was predicted by three software tools, and the result showed that these compounds have good safety profile.

11.
Sci Transl Med ; 15(722): eadg6752, 2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-37967204

RESUMO

T cell immunoglobulin and mucin-containing molecule 3 (Tim-3), expressed in dysfunctional and exhausted T cells, has been widely acknowledged as a promising immune checkpoint target for tumor immunotherapy. Here, using a strategy combining virtual and functional screening, we identified a compound named ML-T7 that targets the FG-CC' cleft of Tim-3, a highly conserved binding site of phosphatidylserine (PtdSer) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). ML-T7 enhanced the survival and antitumor activity of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells and reduced their exhaustion in vitro and in vivo. In addition, ML-T7 promoted NK cells' killing activity and DC antigen-presenting capacity, consistent with the reported activity of Tim-3. ML-T7 strengthened DCs' functions through both Tim-3 and Tim-4, which is consistent with the fact that Tim-4 contains a similar FG-CC' loop. Intraperitoneal dosing of ML-T7 showed comparable tumor inhibitory effects to the Tim-3 blocking antibody. ML-T7 reduced syngeneic tumor progression in both wild-type and Tim-3 humanized mice and alleviated the immunosuppressive microenvironment. Furthermore, combined ML-T7 and anti-PD-1 therapy had greater therapeutic efficacy than monotherapy in mice, supporting further development of ML-T7 for tumor immunotherapy. Our study demonstrates a potential small molecule for selectively blocking Tim-3 and warrants further study.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A , Neoplasias , Humanos , Animais , Camundongos , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Linfócitos T CD8-Positivos , Linfócitos T Citotóxicos/metabolismo , Neoplasias/terapia , Imunoterapia , Microambiente Tumoral
13.
Bioorg Med Chem ; 17(22): 7749-54, 2009 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-19819705

RESUMO

A series of novel 2-(phenylaminocarbonylmethylthio)-6-(2,6-dichlorobenzyl)-pyrimidin-4(3H)-ones have been designed and synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. Most of these new compounds showed moderate to potent activities against wild-type HIV-1 with an EC(50) ranging from 4.48microM to 0.18microM. Among them, 2-[(4-bromophenylamino)carbonylmethylthio]-6-(2,6-dichlorobenzyl)-5-methylpyrimidin-4(3H)-one 4b3 was identified as the most promising compound (EC(50) = 0.18+/-0.06microM, CC(50) >243.56microM, SI >1326). The structure-activity relationship (SAR) of these new congeners is discussed.


Assuntos
Fármacos Anti-HIV/farmacologia , Pirimidinonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/metabolismo , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Pirimidinonas/síntese química , Pirimidinonas/metabolismo , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
14.
Bone ; 40(6): 1462-74, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17376755

RESUMO

GlcNAc N-deacetylase/N-sulfotransferase-1 (NDST-1), a member of the enzyme family catalyzing the first modification step in the biosynthesis of heparan sulfate (HS), was knocked out in mice to investigate its role in embryonic development. NDST-1 null mice exhibited delayed endochondral bone formation including shortened calcified zones in limbs, delayed chondrocyte and osteogenetic differentiation, and increased chondrocyte proliferation. In situ HS binding assay revealed that the binding ability of bone morphogenetic protein (BMP) -2, -4, and -6 to endogenous HS was decreased in mutant phalanges, while that of fibroblast growth factor-1 (FGF-1) was not affected. Up-regulation of BMPR-IA, Phospho-Smad1 (P-Smad1) and parathyroid-hormone related protein (PTHrP), but not the Indian hedgehog, Gli1, Gli3, Patched, and FGFR-3, was observed. Furthermore, block of BMPR signaling with noggin rescued the delayed chondrocyte hypertrophic differentiation in NDST-1 (-/-) mice and recovered the expression of both P-Smad1 and PTHrP proteins. These results suggested that NDST-1-dependent heparan sulfate might negatively modulate BMP and its downstream PTHrP signaling, and thus affect endochondral bone development.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas/metabolismo , Modelos Biológicos , Osteogênese , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Sulfotransferases/metabolismo , Animais , Extremidades/embriologia , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Técnicas de Cultura de Órgãos , Transdução de Sinais , Sulfotransferases/genética
15.
Yao Xue Xue Bao ; 42(10): 1007-12, 2007 Oct.
Artigo em Zh | MEDLINE | ID: mdl-18229603

RESUMO

Human immunodeficiency virus type 1 (HIV-1) transcription is a crucial step in the viral replication cycle, which is considered to be a potential target for inhibition of HIV-1 replication. Among the factors involved in this step, the cellular protein nuclear factor NF-kappaB is the most powerful inducer of HIV-1 transcription. HIV-1 transcription is initiated by the binding of NF-kappaB to the enhancer region in the long terminal repeat (LTR) of HIV-1. Several compounds suppress HIV-1 transcription through the inhibition of NF-kappaB activation. The mechanisms of NF-kappaB in the transcription of HIV-1 and progress of the current inhibitors of NF-kappaB are reviewed.


Assuntos
HIV-1/genética , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Transcrição Gênica/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Repetição Terminal Longa de HIV , Humanos , Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Inibidor de NF-kappaB alfa , Ácidos Nicotínicos/farmacologia , Nitrilas/farmacologia , Replicação Viral
16.
Eur J Med Chem ; 92: 754-65, 2015 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-25626145

RESUMO

In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure-activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos/farmacologia , Nitrogênio/química , Inibidores da Transcriptase Reversa/farmacologia , Sulfonas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Solubilidade , Relação Estrutura-Atividade , Sulfonas/síntese química , Sulfonas/química
17.
FEBS Lett ; 564(1-2): 171-6, 2004 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-15094062

RESUMO

hNRAGE, a neurotrophin receptor p75 interacting MAGE homologue, is cloned from a human placenta cDNA library. hNRAGE can inhibit the colony formation of and arrest cell proliferation at the G1/S and G2/M stages in hNRAGE overexpressing cells. Interestingly, hNRAGE also increases the p53 protein level as well as its phosphorylation (Ser392). Further studies demonstrated that hNRAGE does not affect the proliferation of mouse p53-/- embryonic fibroblasts, suggesting that p53 function is required for hNRAGE induced cell cycle arrest. Moreover, the cell cycle inhibiting protein p21(WAF) is induced by hNRAGE in a p53 dependent manner. The data provide original evidence that hNRAGE arrests cell growth through a p53 dependent pathway.


Assuntos
Interfase , Proteínas de Neoplasias/fisiologia , Transcrição Gênica , Proteína Supressora de Tumor p53/fisiologia , Antígenos de Neoplasias , Divisão Celular , Linhagem Celular Tumoral , Clonagem Molecular , Inibidor de Quinase Dependente de Ciclina p21 , Ciclinas/biossíntese , Regulação da Expressão Gênica , Humanos , Proteínas de Neoplasias/genética , Fosforilação , Transfecção , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
PLoS One ; 7(4): e32554, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22485132

RESUMO

Bone morphogenetic protein (BMP) signaling pathway plays important roles in urinary tract development although the detailed regulation of its activity in this process remains unclear. Here we report that follistatin-like 1 (Fstl1), encoding a secreted extracellular glycoprotein, is expressed in developing ureter and antagonizes BMP signaling activity. Mouse embryos carrying disrupted Fstl1 gene displayed prominent hydroureter arising from proximal segment and ureterovesical junction defects. These defects were associated with significant reduction in ureteric epithelial cell proliferation at E15.5 and E16.5 as well as absence of subepithelial ureteral mesenchymal cells in the urinary tract at E16.5 and E18.5. At the molecular level, increased BMP signaling was found in Fstl1 deficient ureters, indicated by elevated pSmad1/5/8 activity. In vitro study also indicated that Fstl1 can directly bind to ALK6 which is specifically expressed in ureteric epithelial cells in developing ureter. Furthermore, Sonic hedgehog (SHH) signaling, which is crucial for differentiation of ureteral subepithelial cell proliferation, was also impaired in Fstl1(-/-) ureter. Altogether, our data suggest that Fstl1 is essential in maintaining normal ureter development by antagonizing BMP signaling.


Assuntos
Proteínas Morfogenéticas Ósseas/fisiologia , Proteínas Relacionadas à Folistatina/fisiologia , Transdução de Sinais , Ureter/embriologia , Animais , Receptores de Proteínas Morfogenéticas Ósseas Tipo I/metabolismo , Diferenciação Celular , Proliferação de Células , Células Epiteliais/fisiologia , Feminino , Proteínas Relacionadas à Folistatina/genética , Proteínas Relacionadas à Folistatina/metabolismo , Expressão Gênica , Células HEK293 , Proteínas Hedgehog/metabolismo , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ureter/citologia , Ureter/metabolismo , Sistema Urinário/citologia , Sistema Urinário/embriologia , Sistema Urinário/metabolismo
19.
Structure ; 20(10): 1681-91, 2012 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-22902861

RESUMO

To guide development of new drugs targeting methionyl-tRNA synthetase (MetRS) for treatment of human African trypanosomiasis, crystal structure determinations of Trypanosoma brucei MetRS in complex with its substrate methionine and its intermediate product methionyl-adenylate were followed by those of the enzyme in complex with high-affinity aminoquinolone inhibitors via soaking experiments. Drastic changes in conformation of one of the two enzymes in the asymmetric unit allowed these inhibitors to occupy an enlarged methionine pocket and a new so-called auxiliary pocket. Interestingly, a small low-affinity compound caused the same conformational changes, removed the methionine without occupying the methionine pocket, and occupied the previously not existing auxiliary pocket. Analysis of these structures indicates that the binding of the inhibitors is the result of conformational selection, not induced fit.


Assuntos
Aminoquinolinas/química , Antimaláricos/química , Metionina tRNA Ligase/química , Trypanosoma brucei brucei/enzimologia , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/química , Benzimidazóis/química , Domínio Catalítico , Cristalografia por Raios X , Ligação de Hidrogênio , Metionina/análogos & derivados , Metionina/química , Modelos Moleculares , Ligação Proteica , Estrutura Quaternária de Proteína , Estrutura Secundária de Proteína , Subunidades Proteicas/química , Propriedades de Superfície
20.
Curr Med Chem ; 18(16): 2376-85, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21568919

RESUMO

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) bind to an allosteric site on reverse transcriptase (RT) and are a key component of highly active anti-retroviral therapy (HAART) combination regimen for clinical treatment of HIV/AIDS. However, the rapid emergence of drug resistance has limited NNRTIs' clinical option. Therefore, there is an urgent need for the design and development of new and safe NNRTIs that are specifically active against drug-resistant viral strains. DABOs family is one representative of the reported potent HIV-1 NNRTIs, with robust anti-HIV-1 activity against both the wild-type (wt) and drug-resistant isolates carrying multiple RT gene mutations. Three generations of DABO analogues have been studied up to now, i.e.: dihydroalkyloxybenzyloxopyrimidines (O-DABOs), dihydroalkylthiobenzyloxopyrimidines (S-DABOs) and dihydroalkylaminodifluorobenzyloxopyrimidines (N-DABOs), from which many promising DABOs are under developed. The recent research of the DABOs family in antiviral activity, structure activity relationships (SAR), and interaction model with the HIV-1 RT are reviewed in this paper.


Assuntos
Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Pirimidinas/síntese química , Pirimidinas/química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
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