Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 33
Filtrar
1.
Taiwan J Obstet Gynecol ; 63(2): 154-160, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38485307

RESUMO

The relationship between CD276 and malignancies of the female reproductive system has previously been controversial. The purpose of this study was to evaluate the predictive value of CD276 expression in clinicopathological features and prognosis of female reproductive system malignant tumors through meta-analysis. PubMed, Embase, Cochrane Library, Web of Science, CNKI and Wanfang databases were searched for studies published up to December 2022 on the role of CD276 expression in the clinicopathological features and prognosis of female reproductive system malignancies. STATA 14.0 was used for meta-analysis. A total of 10 studies were included, involving 840 patients with malignant tumors of the female reproductive system. The results showed that in terms of clinicopathological features: CD276 expression was closely related to lymph node status [OR = 2.33, 95 %CI = 1.32-4.11, P = 0.003], tumor differentiation [OR = 2.15, 95 %CI = 1.27-3.63, P = 0.004], and FIGO stage [OR = 2.58, 95 %CI = 1.44-4.61, P = 0.001] of reproductive system malignant tumors. In terms of prognosis: CD276 expression is strongly associated with shorter OS in patients with female reproductive system malignancies [HR = 3.33, 95 % CI = 1.36-8.15, P = 0.01]. CD276 may be a new target for immunotherapy and a biomarker for predicting poor prognosis of female reproductive system malignancies.


Assuntos
Neoplasias dos Genitais Femininos , Neoplasias , Humanos , Feminino , Prognóstico , Biomarcadores Tumorais/metabolismo , Bases de Dados Factuais , Genitália Feminina/metabolismo , Genitália Feminina/patologia , Antígenos B7
2.
J Am Chem Soc ; 146(8): 5316-5323, 2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38364304

RESUMO

Efficient synthesis of enantioenriched amines is of great importance due to their significant synthetic and biological applications. Photoredox-mediated asymmetric α-amino C(sp3)-H functionalization offers an atom-economical and sustainable approach to access chiral amines. However, the development of analogous reactions is in its early stages, generally affording chiral amines with a single stereocenter. Herein, we present a novel synergistic triple-catalysis approach for the asymmetric α-C-H addition of readily available N-sulfonyl amines to aldehydes under mild conditions. This method allows for the efficient synthesis of a diverse array of valuable ß-amino alcohols bearing vicinal stereocenters. Unlike previous reports, our protocol employs a radical approach using earth-abundant Cr catalysis. Quinuclidine plays a dual role by facilitating highly selective hydrogen-atom transfer to generate α-amino radicals and promoting the dissociation of the Cr-O bond, which is crucial for the overall catalytic cycle as evidenced by control, NMR, and DFT experiments. Preliminary mechanistic studies, including radical trapping, nonlinear effect, Stern-Volmer plot, kinetic isotope effect, and Hammett plot, offer valuable insights into the reaction pathway.

3.
World J Clin Cases ; 11(29): 7221-7226, 2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37946777

RESUMO

BACKGROUND: Ectopic pancreas may be unfamiliar to many people because it is rare and difficult to diagnose. However, this disease is highly susceptible to misdiagnosis and missed diagnosis. In this article, we report two cases of pancreatic heterotopia in the gastric sinus and small intestine, respectively, both of which were confirmed by histopathological examination. CASE SUMMARY: The first patient was a 43-year-old female which reported abdominal distension for 2 mo. The second was a 67-year-old female who experienced intermittent epigastric discomfort for 15 d. In both cases, there was no confirmed preoperative examination, and the postoperative pathology indicated the presence of ectopic pancreas. CONCLUSION: The diagnosis of ectopic pancreas is difficult, and is often prone to misdiagnosis and the possibility of being overlooked. Various laboratory tests and imaging tests should be carefully evaluated before surgery to achieve early detection, early diagnosis and early treatment.

4.
Nat Commun ; 13(1): 5036, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36028488

RESUMO

The merger of photoredox and transition-metal catalysis has evolved as a robust platform in organic synthesis over the past decade. The stereoselective 1,4-functionalization of 1,3-enynes, a prevalent synthon in synthetic chemistry, could afford valuable chiral allene derivatives. However, tremendous efforts have been focused on the ionic reaction pathway. The radical-involved asymmetric 1,4-functionalization of 1,3-enynes remains a prominent challenge. Herein, we describe the asymmetric three-component 1,4-dialkylation of 1,3-enynes via dual photoredox and chromium catalysis to provide chiral allenols. This method features readily available starting materials, broad substrate scope, good functional group compatibility, high regioselectivity, and simultaneous control of axial and central chiralities. Mechanistic studies suggest that this reaction proceeds through a radical-involved redox-neutral pathway.


Assuntos
Cromo , Catálise , Técnicas de Química Sintética , Oxirredução
5.
Angew Chem Int Ed Engl ; 61(10): e202117114, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35029018

RESUMO

α-Allenol is a versatile synthon in organic synthesis. The catalytic asymmetric synthesis of α-allenols from readily available starting materials remains a prominent challenge, especially when simultaneous control over axial and central chirality is required. Herein, we describe the Cr-catalyzed enantioconvergent allenylation of aldehydes with racemic propargyl halides to rapidly access a wide range of chiral α-allenols with adjacent axial and central chiralities. This method features excellent regio-, diastereo- and enantioselectivity control with broad substrate scope, and provides facile access to all four stereoisomers when allied with a Mitsunobu reaction. Preliminary mechanistic studies support radical-based reaction pathways. The synthetic utility is demonstrated by the application in late-stage functionalization and the formal total synthesis of (+)-varitriol.

6.
Ying Yong Sheng Tai Xue Bao ; 32(12): 4263-4271, 2021 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-34951267

RESUMO

The community characteristics of soil nematodes are an important basis for evaluating and indicating soil health. In this study, cotton fields with different continuous monocropping years (5, 10, 15, 20, and 25 years) were selected. High-throughput sequencing technology was used to explore the responses of soil properties and nematode communities to long-term continuous monocropping in cotton fields. The results showed that after 10-15 years, soil pH and soil conductivity increased significantly, and the contents of soil organic carbon, total nitrogen, available phosphorus (AP), available potassium, nitrate and soil microbial biomass carbon (MBC) decreased significantly. A total of 25 genera, 18 families, 7 orders and 3 classes of soil nematodes were identified. Among them, Helicotylenchus was the dominant genus. Parasitic nematodes were the dominant trophic groups, showing a trend of first decreasing and then increasing. Compared with other continuous monocropping years, plant parasitic nematodes increased by 9.1%-208.6% and Helicotylenchus increased by 392.0% under continuous monocropping for 25 years. With the increases of continuous monocropping duration, plant parasitic nematodes such as Tylenchorhynchus, Ditylenchus, Discopersicus, Mesocriconema, and Criconemoides were detected. After continuous monocropping for 15 years, soil nematode richness index and maturity index of free-living nematodes (MI) decreased significantly, PPI/MI increased significantly, and diversity index (Shannon) and Wasilewska index were the lowest. Soil AP and MBC were the main environmental factors affecting the changes of soil nematode communities. Our results suggested that, after 10-15 years continuous monocropping, soil nutrients were unbalanced, the diversity of soil nematodes was reduced, the stability of soil food network was deteriorated, and the parasitic nematodes were increased, which resulted in continuous monocropping obstacles in cotton.


Assuntos
Nematoides , Solo , Animais , Carbono , China , Humanos , Microbiologia do Solo
7.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(5): 513-518, 2021 May.
Artigo em Chinês | MEDLINE | ID: mdl-34020743

RESUMO

OBJECTIVE: To study the change and significance of serum pentraxin-3 (PTX-3) and syndecan-4 in children with chronic heart failure (CHF). METHODS: A total of 40 children with CHF who were admitted to the Department of Pediatrics of the First Affiliated Hospital of Zhengzhou University were enrolled as the heart failure group, and 30 children who underwent physical examination in the outpatient service during the same period of time were enrolled as the control group. The serum levels of PTX-3, syndecan-4, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were compared between the two groups. RESULTS: The children with CHF had significant reductions in the serum levels of PTX-3, syndecan-4, and NT-proBNP after treatment. The levels of these markers in children with CHF were significantly higher than the control group before and after treatment (P < 0.05). The CHF children with grade II/III/IV cardiac function had significantly higher serum levels of PTX-3 and syndecan-4 than the control group (P < 0.05). The levels of PTX-3 and syndecan-4 were related to the severity of cardiac function. Compared with the grade II cardiac function group, the grade IV cardiac function group had significant increases in the serum levels of PTX-3 and syndecan-4 (P < 0.05). The serum level of PTX-3 was positively correlated with that of syndecan-4 in children with CHF (rs=0.999, P < 0.05); the serum level of PTX-3 was positively correlated with NT-proBNP, left ventricular mass index (LVMI), and cardiac function grade (rs=0.726, 0.736, and 0.934 respectively, P < 0.05) and was negatively correlated with left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (rs=-0.852 and -0.767 respectively, P < 0.05); the serum level of syndecan-4 was positively correlated with NT-proBNP, LVMI, and cardiac function grade (rs=0.733, 0.743, and 0.934 respectively, P < 0.05) and was negatively correlated with LVEF and LVFS (rs=-0.856 and -0.771 respectively, P < 0.05). CONCLUSIONS: Serum PTX-3 and syndecan-4 may be involved in the development and progression of ventricular remodeling in children with CHF and may be used as markers for the diagnosis, cardiac function grading, and treatment outcome evaluation of children with heart failure.


Assuntos
Insuficiência Cardíaca , Sindecana-4 , Biomarcadores , Proteína C-Reativa , Criança , Doença Crônica , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Componente Amiloide P Sérico , Volume Sistólico , Função Ventricular Esquerda
8.
Eur J Med Chem ; 217: 113359, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33725632

RESUMO

A series of highly active CF3-containing 3'-(nitroisoxazole)spiro[pyrrolidin-3,2'-oxindoles] were synthesized and found to be novel glutathione peroxidase 4 (GPX4)/mouse double minute 2 (MDM2) dual inhibitors. Bioactive spirooxindole and isoxazole skeletons were combined, and the resulting compounds exhibited strong activities against both targets. In particular, compound 3d displayed excellent activity in the suppression of MDM2-mediated degradation of p53, as well as levels of GPX4, in MCF-7 breast cancer cells. Moreover, 3d also exhibited inhibitory effects on MDM2 and GPX4 in MCF-7 xenograft model to trigger ferroptotic and apoptotic cell death in in vivo experiments, which was consistent with the results of in vitro experiments.


Assuntos
Antineoplásicos/farmacologia , Desenho de Fármacos , Isoxazóis/farmacologia , Nitrocompostos/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Células MCF-7 , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/metabolismo , Neoplasias Mamárias Experimentais/patologia , Camundongos , Estrutura Molecular , Nitrocompostos/síntese química , Nitrocompostos/química , Oxindóis/química , Oxindóis/farmacologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/química , Pirrolidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade
9.
Zhongguo Dang Dai Er Ke Za Zhi ; 23(1): 84-90, 2021 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-33476543

RESUMO

This article summarizes and analyzes the clinical features and gene mutation characteristics of children with noncompaction of the ventricular myocardium (NVM). For the 6 children with NVM (4 boys and 2 girls), the age of onset ranged from 3 months to 12 years. Of the 6 children, 5 had arrhythmia, 3 had cardiac insufficiency, 1 had poor mental state, and 1 had chest distress and sighing. NVM-related gene mutations were detected in 4 children, among whom 2 had MYH7 gene mutation, 1 had PRDM16 gene mutation, and 1 had mutations in the ACTN2 and TNNT2 genes. Four children had improvement in cardiac function. The two children with no significant improvement in cardiac function had a younger age of onset, a greater reduction in systolic function on echocardiography, and greater increases in myocardial enzyme and N-terminal pro-brain natriuretic peptide. It is concluded that for children with the initial symptoms of chest distress, sighing, arrhythmia, enlarged heart shadow, and increased myocardial enzyme, echocardiography and cardiac magnetic resonance are recommended for the diagnosis of NVM. NVM can have various genetic mutations.


Assuntos
Cardiomiopatias , Ventrículos do Coração , Criança , Pré-Escolar , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Humanos , Lactente , Masculino , Mutação , Miocárdio
10.
Ying Yong Sheng Tai Xue Bao ; 30(4): 1218-1226, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-30994282

RESUMO

A long-term field experiment was conducted to investigate the effects of continuous cotton production years (0 as control, 5, 10, 15 and 20 years) and straw return on soil organic carbon (SOC) structure and stability by using Fourier transform infrared spectroscopy (FTIR) in Manas River valley of Xinjiang. The results showed that the relative peak intensity of polysaccharide and aromatics decreased with increasing continuous cropping years, whereas the aliphatic and alcoholic phenols relative peak intensity and the CH/C=C increased. The content of soil particulate organic carbon (POC) increased significantly in the 5-yr of cotton production farmland and then decreased with the increases of continuous cropping years. POC content was 5.11 times higher in 5-yr than that of the control. The content of mineral-bound organic carbon (MOC) was the highest in 10-yr farmland, being 1.84 times higher than that of the control. The highest value of the ratio of POC and MOC content (ω(POC)/ω(MOC)) was observed in 5-yr farmland. Together, long-term continuous cotton production with straw return led to SOC structure aliphatic and soil mineral binding increased the protection of organic matter, thus increasing the stability of soil organic matter.


Assuntos
Agricultura/métodos , Carbono , Fertilizantes , Gossypium/crescimento & desenvolvimento , Minerais , Solo , Espectroscopia de Infravermelho com Transformada de Fourier
11.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(4): 332-336, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31014424

RESUMO

OBJECTIVE: To study the association of exposure to polycyclic aromatic hydrocarbons (PAH) during pregnancy and autism spectrum disorder (ASD)-related behaviors in toddlers. METHODS: A total of 348 toddlers who had accepted the measurement of PAH-DNA adduct in umbilical cord blood and evaluation of behavior problems at the age of 36 months were enrolled in this birth cohort study. Child Behavior Checklist (CBCL) and Autism Behavior Checklist (ABC) were used to evaluate behavior problems at the age of 36 months. The correlation of the concentration of PAH-DNA adduct in umbilical cord blood with CBCL and ABC scores at the age of 36 months were analyzed. RESULTS: The detection rate of PAH-DNA adduct in umbilical cord blood was 52.3%, and the median concentration was 0.68 ng/mL. The median total scores of CBCL and ABC scales were 23 and 8 respectively. In children aged 36 months, the concentration of PAH-DNA adduct was positively correlated with the score of social withdrawal in the CBCL scale (rs=0.205, P<0.05), the total score of the ABC scale (rs=0.412, P<0.05), and the self-care score of the ABC scale (rs=0.355, P<0.05). The concentration of PAH-DNA adduct was closely associated with the total score of the ABC scale in children aged 36 months (ß=0.122, P<0.05). CONCLUSIONS: PAH exposure during pregnancy may be a risk factor for ASD-related behaviors in toddlers. Effective reduction of PAH exposure during pregnancy and detection of PAH-DNA adduct in neonatal umbilical cord blood are of vital importance for early prevention, screening and intervention of ASD.


Assuntos
Transtorno do Espectro Autista , Hidrocarbonetos Policíclicos Aromáticos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Transtorno do Espectro Autista/induzido quimicamente , Comportamento Infantil , Pré-Escolar , Estudos de Coortes , Feminino , Sangue Fetal , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente
12.
FEBS Open Bio ; 8(7): 1093-1103, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29988590

RESUMO

Despite progress in the treatment of hepatocellular carcinoma (HCC), 5-year survival rates remain low. Thus, a more comprehensive approach to explore the mechanism of HCC is needed to provide new leads for targeted therapy. We performed an integrated analysis to discover the relationship between DNA methylation and gene expression in hepatocellular carcinoma (HCC). DNA methylation and gene expression data for HCC were downloaded from The Cancer Genome Atlas (TCGA) database, and differential analysis was performed. Correlation analysis between DNA methylation and gene expression data was then performed in R language. Finally, we selected several crucial genes and evaluated their potential use as diagnostic biomarkers for HCC. In total, 1135 differentially DNA-methylated CpG sites (DMCs), 377 differentially methylated regions (DMRs), and 1194 differentially expressed genes (DEGs) were identified in HCC. Among the DEGs, 14 genes (ALX3, B4GALNT1,CTHRC1,DLX5,EMX1,IRX3,OTX1,SIX2,TLX1,VASH2,ZIC2,ZIC4,ZIC5, and ZNF695) exhibited changes in DNA methylation in terms of CpG sites or CpG island (CGI) level, of which TLX1 and ZIC4 had the most DMCs (12 and 13, respectively). Further analysis of CTHRC1,ZIC4,SIX2,VASH2,IL17D,TLX1,OTX1, and LART, examining alterations in both DNA methylation and gene expression level in HCC, showed their potential diagnostic value for HCC was better at the gene expression level than that the DNA methylation level. The DNA methylation status of CTHRC1,VASH2, and IL7D was significantly associated with HCC overall survival (P-value <0.05). This systemic analysis identified a group of novel gene signatures (CTHRC1,ZIC4, and OTX1) that may be regulated by DNA hypermethylation, which may be closely associated with HCC.

13.
Eur J Med Chem ; 125: 1051-1063, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-27810592

RESUMO

Currently, three HIV-1 integrase (IN) active site-directed inhibitors are in clinical use for the treatment of HIV infection. However, emergence of drug resistance mutations have limited the promise of a long-term cure. As an alternative, allosteric inhibition of IN activity has drawn great attention and several of such inhibitors are under early stage clinical development. Specifically, inhibitors of IN and the cellular cofactor LEDGF/p75 remarkably diminish proviral integration in cells and deliver a potent reduction in viral replicative capacity. Distinct from the extensively studied 2-(quinolin-3-yl) acetic acid or 1H-indol-3-yl-2-hydroxy-4-oxobut-2-enoic acid chemotypes, this study discloses a new class of selective IN-LEDGF/p75 inhibitors without the carboxylic acid functionality. More significantly, 3-hydroxypicolinamides also show low micromolar inhibition against IN dimerization, providing novel dual IN inhibitors with in vitro therapeutically selective antiviral effect for further development. Finally, our shape-based ROCS pharmacophore model of the 3-hydroxypicolinamide class of compounds provides a new insight into the binding mode of these novel IN-LEDGF/p75 inhibitors.


Assuntos
Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Integrase de HIV/metabolismo , HIV-1/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ácidos Picolínicos/farmacologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Fármacos Anti-HIV/química , Linhagem Celular , Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Simulação de Acoplamento Molecular , Ácidos Picolínicos/química
14.
Yi Chuan ; 38(2): 144-54, 2016 02.
Artigo em Chinês | MEDLINE | ID: mdl-26907778

RESUMO

Recent years have witnessed the rapid development of the clustered regularly interspaced short palindromic repeats/CRISPR-associated protein(CRISPR/Cas9)system. In order to realize gene knockout with high efficiency and specificity in zebrafish, several labs have synthesized distinct Cas9 cDNA sequences which were cloned into different vectors. In this study, we chose two commonly used zebrafish-codon-optimized Cas9 coding sequences (zCas9_bz, zCas9_wc) from two different labs, and utilized them to knockout seven genes in zebrafish embryos, including the exogenous egfp and six endogenous genes (chd, hbegfa, th, eef1a1b, tyr and tcf7l1a). We compared the knockout efficiencies resulting from the two zCas9 coding sequences, by direct sequencing of PCR products, colony sequencing and phenotypic analysis. The results showed that the knockout efficiency of zCas9_wc was higher than that of zCas9_bz in all conditions.


Assuntos
Sistemas CRISPR-Cas , Códon/genética , Embrião não Mamífero/metabolismo , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Sequência de Bases , Embrião não Mamífero/embriologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Dados de Sequência Molecular , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Homologia de Sequência de Aminoácidos , Fatores de Tempo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismo
15.
Zhongguo Zhong Yao Za Zhi ; 41(16): 2998-3001, 2016 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-28920338

RESUMO

The endophytic fungi HL-Y-3, which was isolated from the healthy leaves of Coptis chinensis, produced berberine when grown in the PDA culture medium. The presence of berberine was confirmed by the chromatographic and spectroscopic analyses. The yield of berberine was recorded as 9.313 µg•g⁻¹ by HPLC. The strain HL-Y-3 was identified as Alternaria sp.by morphological observation and 5.8S rDNA-ITS sequence analysis.The separation and purification of constituents were performed by PTLC. The mass spectrometry (MS) of the analyte was shown to be identical with authentic berberine.Further analysis with nuclear magnetic resonance (NMR) spectroscopy to showed that the chemical structure of the fungal berberine was identical with authentic berberine. The research provided new resources for the utilization of berberine.


Assuntos
Alternaria/química , Berberina/isolamento & purificação , Coptis/microbiologia , Cromatografia Líquida de Alta Pressão , Endófitos/química , Folhas de Planta/microbiologia
16.
Mutat Res ; 780: 86-96, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26318124

RESUMO

DNA double-strand break (DSB) repair is of considerable importance for genomic integrity. Homologous recombination (HR) and non-homologous end joining (NHEJ) are considered as two major mechanistically distinct pathways involved in repairing DSBs. In recent years, another DSB repair pathway, namely, microhomology-mediated end joining (MMEJ), has received increasing attention. MMEJ is generally believed to utilize an alternative mechanism to repair DSBs when NHEJ and other mechanisms fail. In this study, we utilized zebrafish as an in vivo model to study DSB repair and demonstrated that efficient MMEJ repair occurred in the zebrafish genome when DSBs were induced using TALEN (transcription activator-like effector nuclease) or CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 technologies. The wide existence of MMEJ repair events in zebrafish embryos was further demonstrated via the injection of several in vitro-designed exogenous MMEJ reporters. Interestingly, the inhibition of endogenous ligase 4 activity significantly increased MMEJ frequency, and the inhibition of ligase 3 activity severely decreased MMEJ activity. These results suggest that MMEJ in zebrafish is dependent on ligase 3 but independent of ligase 4. This study will enhance our understanding of the mechanisms of MMEJ in vivo and facilitate inducing desirable mutations via DSB-induced repair.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades/fisiologia , DNA Ligases/metabolismo , Embrião não Mamífero/enzimologia , Proteínas de Peixe-Zebra/metabolismo , Peixe-Zebra/embriologia , Animais , DNA Ligase Dependente de ATP , DNA Ligases/genética , Proteínas de Ligação a Poli-ADP-Ribose , Proteínas de Xenopus , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
17.
Org Lett ; 16(11): 2822-5, 2014 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-24814536

RESUMO

A fast and simple divergent synthesis of multisubstituted quinazolines and benzimidazoles was developed from readily available amidines, via iodine(III)-promoted oxidative C(sp(3))-C(sp(2)) and C(sp(2))-N bond formation in nonpolar and polar solvents, respectively. Further selective synthesis of quinazolines in polar solvent was realized by TEMPO-catalyzed sp(3)C-H/sp(2)C-H direct coupling of the amidine with K2S2O8 as the oxidant. No metal, base, or other additives were needed.


Assuntos
Amidinas/química , Benzimidazóis/síntese química , Quinazolinas/química , Quinazolinas/síntese química , Benzimidazóis/química , Catálise , Metais , Estrutura Molecular , Oxidantes , Solventes/química
18.
Bioorg Med Chem ; 22(12): 3146-58, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24794743

RESUMO

HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their ß-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50=0.826 µg/mL) and high therapeutic index (TI>242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low- to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antivirais/farmacologia , Cromonas/farmacologia , Desenho de Fármacos , Descoberta de Drogas , Flavonoides/química , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/química , Morfolinas/farmacologia , Proteínas Oncogênicas v-fos/metabolismo , Fatores de Transcrição/metabolismo , Antivirais/síntese química , Domínio Catalítico , Cromonas/síntese química , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , HIV-1/efeitos dos fármacos , Humanos , Estrutura Molecular , Morfolinas/síntese química , Relação Estrutura-Atividade
19.
Int J Gynecol Cancer ; 24(3): 534-40, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24557437

RESUMO

OBJECTIVE: AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that encodes the BAF250a protein. Recent studies have shown the loss of ARID1A expression in several types of tumors. We aimed to investigate the clinical and pathologic role of BAF250a in endometrial carcinoma. METHODS: We examined the expression of BAF250a and its correlation with the expression of p53, estrogen receptor, progesterone receptor, glucocorticoid receptor, hypoxiainduciblefactor-1α, and vascular endothelial growth factor in normal and various malignant endometrial tissues. RESULTS: The expression of BAF250 was significantly down-regulated in endometrial carcinoma when compared with normal endometrial tissues. The loss of BAF250a expression was found in 25% of endometrial carcinoma samples but not in normal endometrial tissues, complex endometrial hyperplasia, and atypical endometrial hyperplasia samples. Subtypes of endometrial carcinoma, especially uterine endometrioid carcinoma and uterine clear cell carcinoma, had higher frequency of loss of BAF250a expression. In addition, the expression of BAF250a was positively correlated with estrogen receptor and negatively correlated with p53 in poorly differentiated endometrial adenocarcinoma. Moreover, the expression of BAF250a was significantly associated with the differentiation status of endometrial carcinoma but not associated with clinical stage, the depth of myometrial invasion, lymph node metastasis, and overall survival of patients with endometrial carcinoma. CONCLUSIONS: Our data showed that loss of BAF250a is frequently found in high-grade endometrioid and clear cell carcinomas but not in other types of endometrial carcinoma. The loss of BAF250a expression does not have prognostic value for endometrial carcinoma.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma/patologia , Neoplasias do Endométrio/patologia , Endométrio/patologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Proteínas de Ligação a DNA , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , Endométrio/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
20.
Planta Med ; 79(9): 744-52, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23700113

RESUMO

The traditional Chinese medicinal herb Danshen (Salvia miltiorrhiza), first recorded in the "Shen Nong's Herbal Classic", has long been used to treat cardiovascular conditions, although the mechanism(s) underlying its effects remain unclear. Here, an iron dextran injection (50 mg · kg⁻¹ per day) was delivered intraperitoneally to establish a mouse model for investigating the ameliorative effects of Danshen injection (low dose at 3 g · kg⁻¹ per day or high dose at 6 g · kg⁻¹ per day) on iron overload-induced cardiac damage. The iron-chelating agent deferoxamine (100 mg · kg⁻¹ per day) was administered as a positive control. The main constituents of Danshen injection, salvianic acid A (danshensu), protocatechuic aldehyde, and salvianolic acid B, were quantified at concentrations of 2.15, 0.44, and 1.01 mg · mL⁻¹, respectively, using HPLC with UV detection. Danshen injection significantly lowered cardiac iron deposition and the concentration of the lipid oxidation product malondialdehyde, as well as improved cardiac superoxide dismutase and glutathione peroxidase levels in iron-overloaded mice. Serum levels of creatine kinase, creatine kinase isoenzyme, and lactate dehydrogenase in the iron-overloaded mice were significantly elevated (up to ~ 160 %), whereas their activities were downregulated by Danshen injection by 25 ~ 35 % at the high dose and by ~ 20 % at the low dose. Morphological changes of cardiac tissue analyzed by hematoxylin and eosin staining indicated that lesions induced by iron overload could be ameliorated by Danshen injection dose-dependently. Altogether, these results illustrated that the protective effects of Danshen injection were at least in part due to decreased iron deposition and inhibition of lipid peroxidation.


Assuntos
Medicamentos de Ervas Chinesas/farmacologia , Coração/efeitos dos fármacos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/fisiopatologia , Fenantrolinas/farmacologia , Salvia miltiorrhiza/química , Animais , Benzaldeídos/análise , Benzaldeídos/farmacologia , Benzofuranos/análise , Benzofuranos/farmacologia , Catecóis/análise , Catecóis/farmacologia , Cromatografia Líquida de Alta Pressão , Creatina Quinase/sangue , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/química , Glutationa Peroxidase/metabolismo , Injeções Intraperitoneais , L-Lactato Desidrogenase/sangue , Lactatos/análise , Lactatos/farmacologia , Masculino , Medicina Tradicional Chinesa/métodos , Camundongos , Miocárdio/enzimologia , Miocárdio/patologia , Fenantrolinas/química , Superóxido Dismutase/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...