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1.
Toxicol Appl Pharmacol ; 437: 115886, 2022 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-35041852

RESUMO

Many small molecule kinase inhibitors (SMKIs), used predominantly in cancer therapy, have been implicated in serious clinical cardiac adverse events, which means that traditional preclinical drug development assays were not sufficient for identifying these cardiac liabilities. To improve clinical cardiac safety predictions, the effects of SMKIs targeting many different signaling pathways were studied using human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) in combined assays designed for the detection of both electrophysiological (proarrhythmic) and non-electrophysiological (non-proarrhythmic) drug-induced cardiotoxicity. Several microplate-based assays were used to quantitate cell death, apoptosis, mitochondrial damage, energy depletion, and oxidative stress as mechanism-based non-electrophysiological cardiomyocyte toxicities. Microelectrode arrays (MEA) were used to quantitate in vitro arrhythmic events (iAEs), field potential duration (FPD) prolongation, and spike amplitude suppression (SAS) as electrophysiological effects. To enhance the clinical relevance, SMKI-induced cardiotoxicities were compared by converting drug concentrations into multiples of reported clinical maximum therapeutic plasma concentration, "FoldCmax", for each assay. The results support the conclusion that the combination of the hPSC-CM based electrophysiological and non-electrophysiological assays have significantly more predictive value than either assay alone and significantly more than the current FDA-recommended hERG assay. In addition, the combination of these assays provided mechanistic information relevant to cardiomyocyte toxicities, thus providing valuable information on potential drug-induced cardiotoxicities early in drug development prior to animal and clinical testing. We believe that this early information will be helpful to guide the development of safer and more cost-effective drugs.


Assuntos
Miócitos Cardíacos/efeitos dos fármacos , Células-Tronco Pluripotentes/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Diferenciação Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Inibidores de Proteínas Quinases/química , Receptores de Fatores de Crescimento/genética , Receptores de Fatores de Crescimento/metabolismo
2.
Int J Cancer ; 149(1): 127-138, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33586134

RESUMO

The population of patients with huge hepatocellular carcinoma (H-HCC diameter > 10.0 cm) is an odd group that is not well adjudicated in the current staging systems, whose prognosis after curative resection varies. We aimed to develop novel models to predict the long-term outcomes of patients with H-HCC without portal vein tumor thrombus after hepatectomy. There were 1076 H-HCC patients enrolled who underwent curative liver resection in five institutions in China. In total, 670 patients were recruited from our center and randomly divided into the training cohort (n = 502) and internal validation (n = 168) cohorts. Additionally, 406 patients selected from other four centers as the external validation cohort. Novel models were constructed based on independent preoperative and postoperative predictors of postsurgical recurrence (PSR) and postsurgical mortality (PSM) determined in multivariable cox regression analysis. The predictive accuracy and discriminative ability of the model were measured using Harrell's concordance index (C index) and calibration curve and compared with five conventional HCC staging systems. PSR model and PSM model were constructed based on tumor number, microscopic vascular invasion, tumor differentiation, preoperative alpha-fetoprotein level, albumin-bilirubin grade, liver segment invasion, neutrophil-to-lymphocyte ratio or platelet-to-neutrophil ratio, and surgical margin or intraoperative blood transfusion. The C-indexes were 0.84 (95% CI, 0.78-0.90) and 0.85 (95% CI, 0.78-0.91) for the PSR and PSM models, respectively, which were substantially higher than those of the five conventional HCC staging systems (0.63-0.75 for PSR; 0.66-0.77 for PSM). The two novel models achieved more accurate prognostic predictions of PSR and PSM for H-HCC patients after curative liver resection.


Assuntos
Carcinoma Hepatocelular/patologia , Hepatectomia/mortalidade , Neoplasias Hepáticas/patologia , Modelos Estatísticos , Recidiva Local de Neoplasia/patologia , Nomogramas , Carcinoma Hepatocelular/cirurgia , China , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
3.
Oncologist ; 25(10): e1552-e1561, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32663354

RESUMO

BACKGROUND: The predictive model of postsurgical recurrence for solitary early hepatocellular carcinoma (SE-HCC) is not well established. The aim of this study was to develop a novel model for prediction of postsurgical recurrence and survival for patients with hepatitis B virus (HBV)-related SE-HCC ≤10 cm. PATIENTS AND METHODS: Data from 1,081 patients with HBV-related SE-HCC ≤10 cm who underwent curative liver resection from 2003 to 2016 in our center were collected retrospectively and randomly divided into the derivation cohort (n = 811) and the internal validation cohort (n = 270). Eight hundred twenty-three patients selected from another four tertiary hospitals served as the external validation cohort. Postsurgical recurrence-free survival (RFS) and overall survival (OS) predictive nomograms were generated. The discriminatory accuracies of the nomograms were compared with six conventional hepatocellular carcinoma (HCC) staging systems. RESULTS: Tumor size, differentiation, microscopic vascular invasion, preoperative α-fetoprotein, neutrophil-to-lymphocyte ratio, albumin-to-bilirubin ratio, and blood transfusion were identified as the risk factors associated with RFS and OS. RFS and OS predictive nomograms based on these seven variables were generated. The C-index was 0.83 (95% confidence interval [CI], 0.79-0.87) for the RFS-nomogram and 0.87 (95% CI, 0.83-0.91) for the OS-nomogram. Calibration curves showed good agreement between actual observation and nomogram prediction. Both C-indices of the two nomograms were substantially higher than those of the six conventional HCC staging systems (0.54-0.74 for RFS; 0.58-0.76 for OS) and those of HCC nomograms reported in literature. CONCLUSION: The novel nomograms were shown to be accurate at predicting postoperative recurrence and OS for patients with HBV-related SE-HCC ≤10 cm after curative liver resection. IMPLICATIONS FOR PRACTICE: This multicenter study proposed recurrence or mortality predictive nomograms for patients with hepatitis B virus-related solitary early hepatocellular carcinoma ≤10 cm after curative liver resection. A close postsurgical surveillance protocol and adjuvant therapy should be considered for patients at high risk of recurrence.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Trombose , Carcinoma Hepatocelular/cirurgia , Hepatectomia , Vírus da Hepatite B , Humanos , Neoplasias Hepáticas/cirurgia , Recidiva Local de Neoplasia , Nomogramas , Prognóstico , Estudos Retrospectivos
4.
Bioorg Chem ; 100: 103907, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32413631

RESUMO

The design and synthesis of novel coumarin-thiazolyl ester derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Salmonella. Compound 8p exhibited excellent antibacterial activity against four bacteria strains with MIC values of 0.05, 0.05, 8, and 0.05 µg/mL, respectively. In vitro drug-resistant bacterial inhibition experiments indicated that compound 8p exhibited the best bacteriostatic effect in the selected compounds and four positive control drugs with MIC values of 4 µg/mL. In vitro enzyme inhibitory assay showed that compound 8p exhibited potent inhibition against DNA gyrase with IC50 values of 0.13 µM. The molecular docking model indicated that compounds 8p can bind well to the DNA gyrase by interacting with amino acid residues. This study demonstrated that the compound 8p can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.


Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/enzimologia , Cumarínicos/química , Cumarínicos/farmacologia , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Cumarínicos/síntese química , Desenho de Fármacos , Ésteres/síntese química , Ésteres/química , Ésteres/farmacologia , Humanos , Simulação de Acoplamento Molecular , Tiazóis/síntese química , Tiazóis/química , Tiazóis/farmacologia , Inibidores da Topoisomerase II/síntese química
5.
Bioorg Chem ; 99: 103807, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32272364

RESUMO

The design and synthesis of novel multi-substituted benzo-indole pyrazole Schiff base derivatives of potent DNA gyrase inhibitory activity were the main aims of this study. All the novel synthesized compounds were examined for their antibacterial activities against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella. In addition, we selected 20 compounds for the in vitro antibacterial activities assay of 6 drug-resistant bacteria strains. The result revealed compound 8I-w exhibited excellent antibacterial activity against 4 drug-resistant E. coli bacteria strains with IC50 values of 7.0, 17.0, 13.5, and 1.0 µM, respectively. In vitro enzyme inhibitory assay showed that compound 8I-w displayed potent inhibition against DNA gyrase with IC50 values of 0.10 µM. The molecular docking model indicated that compounds 8I-w can bind well to the DNA gyrase by interacting with various amino acid residues. This study demonstrated that the compound 8I-w can act as the most potent DNA gyrase inhibitor in the reported series of compounds and provide valuable information for the commercial DNA gyrase inhibiting bactericides.


Assuntos
Antibacterianos/farmacologia , DNA Girase/metabolismo , Descoberta de Drogas , Indóis/farmacologia , Pirazóis/farmacologia , Inibidores da Topoisomerase II/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Indóis/síntese química , Indóis/química , Listeria monocytogenes/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Salmonella/efeitos dos fármacos , Bases de Schiff/síntese química , Bases de Schiff/química , Bases de Schiff/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/síntese química , Inibidores da Topoisomerase II/química
6.
Pestic Biochem Physiol ; 163: 271-279, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31973867

RESUMO

In this work, a total of 36 novel 5-(nicotinamido)-1-phenyl-1H-pyrazole-4-carboxylic acid derivatives were designed and synthesized successfully by introducing a carboxyl group based on the N-(1-(4-chlorophenyl)-4-cyano-1H-pyrazol-5-yl)-6-methoxynicotinamide. Among them, the growth inhibition assays on agar plates showed that compound 5IV-d(5-(2-chloronicotinamido)-1-(p-tolyl)-1H-pyrazole-4-carboxylic acid) exhibited the significant antifungal activity against four important fruit and main crop disease fungi (i.e., Valsa mali Miyabe et Yamada, Botryosphaeria dothidea, Helminthosporium maydis and Rhizoctonia cerealis) with EC50 values of 22.6, 14.5, 17.6 and 18.2 µM, respectively. In addition, 5IV-d showed the excellent inhibitory effect against SDH enzymes with IC50 values ranging from 9.4 to 15.6 µM. In vivo bioassay and molecular docking were applied to explore the potential in practical application and combination of modified structure and SDH. The results of structure-activity relationships indicates that the methoxy substitution at the benzene ring attached to the pyrazole ring and a wide variety of substituents could be responsible for the promising antifungal efficacy of the designed compounds. This study demonstrated that the compound 5IV-d can act as the most potent SDH inhibitor in the reported series of compounds.


Assuntos
Rhizoctonia , Succinato Desidrogenase , Antifúngicos , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade
7.
HPB (Oxford) ; 22(2): 289-297, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31405776

RESUMO

BACKGROUND: Morbidity remains a common problem following hepatic resection. The aim of this study was to investigate the association between preoperative body mass index (BMI) and morbidity in patients undergoing liver resection for hepatocellular carcinoma (HCC). METHODS: Patients were divided into three groups according to preoperative BMI: low-BMI (≤18.4 kg/m2), normal-BMI (18.5-24.9 kg/m2) and high-BMI (≥25.0 kg/m2). Baseline characteristics, operative variables, postoperative 30-day mortality and morbidity were compared. Univariable and multivariable analyses were performed to identify independent risk factors associated with postoperative morbidity. RESULTS: Among 1324 patients, 108 (8.2%), 733 (55.4%), and 483 (36.5%) were low-BMI, normal-BMI, and high-BMI, respectively. There were no differences in postoperative 30-day mortality among patients based on BMI (P = 0.199). Postoperative 30-day morbidity was, however, higher in low-BMI and high-BMI patients versus patients with a normal-BMI (33.3% and 32.1% vs. 22.9%, P = 0.018 and P < 0.001, respectively). Following multivariable analysis low-BMI and high-BMI remained independently associated with an increased risk of postoperative morbidity (OR: 1.701, 95%CI: 1.060-2.729, P = 0.028, and OR: 1.491, 95%CI: 1.131-1.966, P = 0.005, respectively). Similar results were noted in the incidence of postoperative 30-day surgical site infection (SSI). CONCLUSION: Compared with normal-BMI patients, low-BMI and high-BMI patients had higher postoperative morbidity, including a higher incidence of SSI after liver resection for HCC.


Assuntos
Índice de Massa Corporal , Carcinoma Hepatocelular/cirurgia , Hepatectomia/efeitos adversos , Neoplasias Hepáticas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Carcinoma Hepatocelular/complicações , China , Bases de Dados Factuais , Feminino , Humanos , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco
8.
Circulation ; 138(22): 2559-2568, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30571346

RESUMO

BACKGROUND: The biased T helper-2 (Th2) response plays a critical role in myocarditis. Bcl2-like protein 12 (Bcl2L12) is associated with the Th2 pattern of inflammation. This study aims to elucidate the role of Bcl2L12 in the pathogenesis of Th2-biased inflammation in the heart. METHODS: Mice were treated with the myosin heavy-chain-α peptides to induce inflammation in the heart. Human hearts were collected from the surgically removed hearts of patients who had undergone heart transplantation. RESULTS: The expression of Bcl2L12 was detected in CD4+ T cells of the hearts, which was markedly higher in the hearts with myocarditis at the advanced stage of heart failure compared with the control (dilated cardiomyopathy) hearts without myocarditis. Mice with Bcl2L12-deficient CD4+ T cells failed to induce the Th2-biased inflammation in the heart. CD4+ T cells with a higher expression of Bcl2L12 were prone to differentiate into Th2 cells. Bcl2L12 formed a complex with GATA3 in CD4+ T cells to enhance the binding between GATA3 and the Il4 promoter, which promoted the Il4 gene transcription. Bcl2L12 compromised the apoptotic machinery by inhibiting the expression of p53 in CD4+ T cells to reduce the activation-induced CD4+ T cell death. CONCLUSIONS: CD4+ T cells isolated from hearts with myocarditis at the end stage of heart failure express high levels of Bcl2L12, and the latter is required for the development of aberrant Th2 polarization in the heart. The Bcl2L12 may be a novel target in the treatment of myocarditis as well as other Th2-biased inflammation.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Interleucina-4/metabolismo , Miocárdio/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Células Th2/metabolismo , Adulto , Animais , Apoptose , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Fator de Transcrição GATA3/metabolismo , Humanos , Interleucina-4/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Miocardite/metabolismo , Miocardite/patologia , Miocárdio/citologia , Miocárdio/imunologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Células Th2/citologia , Células Th2/imunologia , Proteína Supressora de Tumor p53/metabolismo
9.
Mol Divers ; 23(2): 299-306, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30168050

RESUMO

A series of novel Mannich base derivatives of flavone containing benzylamine moiety was synthesized using the Mannich reaction. The results of antifungal activity are not ideal, but its antifungal effect has a certain increase compared to flavonoids. After that, four bacteria were used to test antibacterial experiments of these compounds; compound 5g (MIC = 0.5, 0.125 mg/L) showed significant inhibitory activity against Staphylococcus aureus and Salmonella gallinarum compared with novobiocin (MIC = 2, 0.25 mg/L). Compound 5s exhibited broad spectrum antibacterial activity (MIC = 1, 0.5, 2, 0.05 mg/L) against four bacteria. The selected compounds 5g and 5s exhibit potent inhibition against Topo II and Topo IV with IC50 values (0.25-16 mg/L). Molecular docking model showed that the compounds 5g and 5s can bind well to the target by interacting with amino acid residues. It will provide some valuable information for the commercial antibacterial agents.


Assuntos
Antibacterianos , DNA Topoisomerase IV/antagonistas & inibidores , Flavonas , Bases de Mannich , Inibidores da Topoisomerase II , Antibacterianos/química , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/crescimento & desenvolvimento , Desenho de Fármacos , Flavonas/química , Flavonas/farmacologia , Gibberella/efeitos dos fármacos , Gibberella/crescimento & desenvolvimento , Bases de Mannich/química , Bases de Mannich/farmacologia , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
10.
Molecules ; 24(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987179

RESUMO

To develop new antibacterial agents, a series of novel triazole-containing pyrazole ester derivatives were designed and synthesized and their biological activities were evaluated as potential topoisomerase II inhibitors. Compound 4d exhibited the most potent antibacterial activity with Minimum inhibitory concentration (MIC) alues of 4 µg/mL, 2 µg/mL, 4 µg/mL, and 0.5 µg/mL against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Salmonella gallinarum, respectively. The in vivo enzyme inhibition assay 4d displayed the most potent topoisomerase II (IC50 = 13.5 µg/mL) and topoisomerase IV (IC50 = 24.2 µg/mL) inhibitory activity. Molecular docking was performed to position compound 4d into the topoisomerase II active site to determine the probable binding conformation. In summary, compound 4d may serve as potential topoisomerase II inhibitor.


Assuntos
Antibacterianos/química , Pirazóis/química , Triazóis/química , Antibacterianos/farmacologia , DNA Girase/química , Ésteres , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Pirazóis/farmacologia , Relação Estrutura-Atividade , Inibidores da Topoisomerase II/química , Inibidores da Topoisomerase II/farmacologia
11.
Crit Rev Eukaryot Gene Expr ; 28(4): 285-310, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30311578

RESUMO

Articular cartilage defects have very limited self-repair potential, and traditional bone marrow-stimulating therapy is not effective. Cartilage tissue engineering using bone marrow mesenchymal stem cells (BMSCs) and adipose tissue-derived mesenchymal stem cells (ADSCs) is considered an attractive treatment for cartilage lesions and osteoarthritis. However, studies proved that both BMSCs and ADSCs have their own advantages and shortcomings, including their sources, isolation methods, characterizations and differentiation potential. Understanding the properties and differences between ADSCs and BMSCs is important for clinical application in cartilage regeneration. This review provides an overview of BMSCs and ADSCs based on their characterization, isolation. Then, we summarized their differentiation potential in different experimental conditions. Finally, we discuss the applications of BMSCs and ADSCs in scaffold-free and scaffold-based cartilage tissue engineering. Based on different properties of BMSCs and ADSCs, and patient's physical condition, a more suitable therapeutic strategy can be selected.


Assuntos
Tecido Adiposo/citologia , Células da Medula Óssea/citologia , Cartilagem/fisiologia , Células-Tronco Mesenquimais/citologia , Engenharia Tecidual/métodos , Animais , Biomarcadores/metabolismo , Cartilagem/citologia , Diferenciação Celular , Humanos , Células-Tronco Mesenquimais/fisiologia
13.
Arch Biochem Biophys ; 657: 8-14, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30217509

RESUMO

The immune dysregulation plays an important role in the pathogenesis of ulcerative colitis (UC). Bcl2 like protein-12 (Bcl2L12) and mast cells are involved in immune dysregulation of UC. This study aims to elucidate the role of Bcl2L12 in the contribution to the pathogenesis of T helper (Th)2-biased inflammation in UC patients. The results showed that Bcl2L12 was expressed by peripheral CD4+ T cells that was associated with Th2 polarization in UC patients. Bcl2L12 mediated the protease-activated receptor-2 (PAR2)-induced IL-4 expression in CD4+ cells. Activation of PAR2 increased expression of Bcl2L12 in CD4+ T cells. Bcl2L12 mRNA decayed spontaneously in CD4+ T cells after separated from UC patients which was prevented by activating PAR2. Bcl2L12 mediated the binding between GATA3 and the Il4 promoter in CD4+ T cells. Mice with Bcl2L12 deficiency failed to induce Th2-biased inflammation in the colon mucosa. We conclude that CD4+ T cells from UC patients expressed high levels of Bcl2L12; the latter plays an important role in the development of Th2-biased inflammation in the intestine. Bcl2L12 may be a novel therapeutic target in the treatment of Th2-biased inflammation.


Assuntos
Colite Ulcerativa/etiologia , Proteínas Musculares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Células Th2/metabolismo , Adulto , Animais , Linfócitos T CD4-Positivos/metabolismo , Colo/metabolismo , Citocinas/metabolismo , Feminino , Fator de Transcrição GATA3/metabolismo , Humanos , Inflamação/metabolismo , Mucosa Intestinal/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteínas Musculares/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Receptor PAR-2
14.
Chem Pharm Bull (Tokyo) ; 66(4): 358-362, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29607900

RESUMO

Acetohydroxy acid synthase (AHAS; EC 2.2.1.6, also referred to as acetolactate synthase, ALS) has been considered as an attractive target for the design of herbicides. In this work, an optimized pyrazole sulfonamide base scaffold was designed and introduced to derive novel potential AHAS inhibitors by introducing a pyrazole ring in flucarbazone. The results of in vivo herbicidal activity evaluation indicates compound 3b has the most potent activity with rape root length inhibition values of 81% at 100 mg/L, and exhibited the best inhibitory ability against Arabidopsis thaliana AHAS. With molecular docking, compound 3b insert into Arabidopsis thaliana AHAS stably by an H-bond with Arg377 and cation-π interactions with Arg377, Trp574, Tyr579. This study suggests that compound 3b may serve as a potential AHAS inhibitor which can be used as a novel herbicides and provides valuable clues for the further design and optimization of AHAS inhibitors.


Assuntos
Acetolactato Sintase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Sulfonamidas/farmacologia , Acetolactato Sintase/metabolismo , Arabidopsis/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química
15.
Drug Dev Res ; 79(6): 307-312, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30256430

RESUMO

Hit, Lead & Candidate Discovery To discover succinate dehydrogenase inhibitors with a novel structure, we introduced cinnamic acid structure to optimize the lead structure 1 and synthesized four series of cinnamon-pyrazole carboxamide derivatives. The bioassay data showed that compounds (E)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl)-3-(2-fluorophenyl) acrylamide (5III-d) and (E)-3-(2-chlorophenyl)-N-(1-[4-chlorophenyl]-4-cyano-1H-pyrazol-5-yl) acrylamide (5III-f) showed the significant antifungal activity against three fungi. In addition, 5III-d and 5III-f exhibited the excellent inhibitory effect against succinate dehydrogenase (SDH) enzymes with IC50 values ranging from 19.4 to 28.7 µM. The study demonstrates that the chlorine substituent group is present on both the phenyl and pyrazole rings that have a very good effect on the antifungal effect, and the compounds 5III-d and 5III-f can act as potential SDH inhibitors (SDHI) and throw a sprat for a new generation of SDHI.


Assuntos
Carboxina/análogos & derivados , Doenças das Plantas/terapia , Antifúngicos , Carboxina/química , Carboxina/farmacologia , Cinamatos , Colletotrichum/efeitos dos fármacos , Desenho de Fármacos , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Rhizoctonia/efeitos dos fármacos
16.
J Integr Plant Biol ; 60(6): 514-528, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29393579

RESUMO

Xylan is the major plant hemicellulosic polysaccharide in the secondary cell wall. The transcription factor KNOTTED-LIKE HOMEOBOX OF ARABIDOPSIS THALIANA 7 (KNAT7) regulates secondary cell wall biosynthesis, but its exact role in regulating xylan biosynthesis remains unclear. Using transactivation analyses, we demonstrate that KNAT7 activates the promoters of the xylan biosynthetic genes, IRREGULAR XYLEM 9 (IRX9), IRX10, IRREGULAR XYLEM 14-LIKE (IRX14L), and FRAGILE FIBER 8 (FRA8). The knat7 T-DNA insertion mutants have thinner vessel element walls and xylary fibers, and thicker interfascicular fiber walls in inflorescence stems, relative to wild-type (WT). KNAT7 overexpression plants exhibited opposite effects. Glycosyl linkage and sugar composition analyses revealed lower xylan levels in knat7 inflorescence stems, relative to WT; a finding supported by labeling of inflorescence walls with xylan-specific antibodies. The knat7 loss-of-function mutants had lower transcript levels of the xylan biosynthetic genes IRX9, IRX10, and FRA8, whereas KNAT7 overexpression plants had higher mRNA levels for IRX9, IRX10, IRX14L, and FRA8. Electrophoretic mobility shift assays indicated that KNAT7 binds to the IRX9 promoter. These results support the hypothesis that KNAT7 positively regulates xylan biosynthesis.


Assuntos
Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Regulação da Expressão Gênica de Plantas , Pentosiltransferases/genética , Proteínas Repressoras/metabolismo , Xilanos/biossíntese , Vias Biossintéticas/genética , Parede Celular/metabolismo , Perfilação da Expressão Gênica , Inflorescência/genética , Modelos Biológicos , Mutação/genética , Plantas Geneticamente Modificadas , Regiões Promotoras Genéticas , Ligação Proteica/genética , Açúcares/metabolismo
17.
New Phytol ; 213(4): 1667-1681, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28164334

RESUMO

Recent studies indicate that the ETHYLENE RESPONSE FACTOR VII (ERF-VII) transcription factor is an important regulator of osmotic and hypoxic stress responses in plants. However, the molecular mechanism of ERF-VII-mediated transcriptional regulation remains unclear. Here, we investigated the role of ERF74 (a member of the ERF-VII protein family) by examining the abiotic stress tolerance of an ERF74 overexpression line and a T-DNA insertion mutant using flow cytometry, transactivation and electrophoretic mobility shift assays. 35S::ERF74 showed enhanced tolerance to drought, high light, heat and aluminum stresses, whereas the T-DNA insertion mutant erf74 and the erf74;erf75 double mutant displayed higher sensitivity. Using flow cytometry analysis, we found that erf74 and erf74;erf75 lines lack the reactive oxygen species (ROS) burst in the early stages of various stresses, as a result of the lower expression level of RESPIRATORY BURST OXIDASE HOMOLOG D (RbohD). Furthermore, ERF74 directly binds to the promoter of RbohD and activates its expression under different abiotic stresses. Moreover, induction of stress marker genes and ROS-scavenging enzyme genes under various stress conditions is dependent on the ERF74-RbohD-ROS signal pathway. We propose a pathway that involves ERF74 acting as an on-off switch controlling an RbohD-dependent mechanism in response to different stresses, subsequently maintaining hydrogen peroxide (H2 O2 ) homeostasis in Arabidopsis.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , NADPH Oxidases/metabolismo , Explosão Respiratória , Estresse Fisiológico , Arabidopsis/genética , Arabidopsis/efeitos da radiação , Proteínas de Arabidopsis/genética , Sequência de Bases , Secas , Regulação da Expressão Gênica de Plantas/efeitos da radiação , Genes Dominantes , Luz , Modelos Biológicos , Mutação/genética , Fenótipo , Pigmentação/efeitos da radiação , Folhas de Planta/fisiologia , Folhas de Planta/efeitos da radiação , Ligação Proteica/efeitos da radiação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória/efeitos da radiação , Estresse Fisiológico/genética , Estresse Fisiológico/efeitos da radiação , Ativação Transcricional/genética
18.
Bioorg Med Chem ; 24(19): 4652-4659, 2016 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-27515719

RESUMO

Mitogen activated protein kinase (MAPK) signal transduction pathway has been proved to play an important role in tumorigenesis and cancer development. MEK inhibitor has been demonstrated significant clinical benefit for blocking MAPK pathway activation and possibly could block reactivation of the MAPK pathway at the time of BRAF inhibitor resistance. Twenty N-(benzyloxy)-1,3-diphenyl-1H-pyrazole-4-carboxamide derivatives have been designed and synthesized as MEK inhibitors, and their biological activities were evaluated. Among these compounds, compound 7b showed the most potent inhibitory activity with IC50 of 91nM for MEK1 and GI50 value of 0.26µM for A549 cells. The SAR analysis and docking simulation were performed to provide crucial pharmacophore clues that could be used in further structure optimization.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Relação Quantitativa Estrutura-Atividade
19.
Chem Pharm Bull (Tokyo) ; 64(12): 1755-1762, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27725363

RESUMO

Acetylcholinesterase (AChE) is a key enzyme which present in the central nervous system of living organisms. Organophosphorus pesticides (OPs) that serve as insecticides are AChE inhibitors which have been used widely in agriculture. A series of novel OPs containing pyrazole moiety have been designed and synthesized. The biological evaluation indicated compound 4e appeared 81% larvicidal activity against Plutella xylostella at the concentration of 0.1 mg/L and the inhibition of AChE by compound 4e was distinctly enhanced with the increasing doses. Molecular docking of compound 4e into the three dimensional X-ray structure of the Drosophila melanogaster AChE (DmAChE, PDB code: 1QO9) was carried out utilizating the Discovery Studio (DS), the binding model revealed that the title structure was tightly embedded in the binding sites of DmAChE. Therefore, we suggest that compound 4e may serve as a novel AChE inhibitor that can be utilized as a new insecticidal drug.


Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Inseticidas/farmacologia , Mariposas/efeitos dos fármacos , Organofosfonatos/química , Organofosfonatos/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Inseticidas/síntese química , Inseticidas/química , Simulação de Acoplamento Molecular , Mariposas/enzimologia , Organofosfonatos/síntese química , Relação Estrutura-Atividade
20.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(7): 2022-6, 2016 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-30035864

RESUMO

Mo-doped zinc oxide (ZnO∶Mo) films were deposited with direct current magnetron sputtering on quartz substrates at room temperature. The effects of Mo doping content on the crystal structure, surface microstructure,optical properties and plasmon characteristics of the ZnO films were investigated with X-ray diffraction(XRD),atomic force microscopy (AFM),Spectrophotometer and Raman spectrometer. The XRD pattern reveals that pure ZnO film exhibits good crystallization and c-axis oriented while heavy doping leads to increasing film defects. That results decline the film crystalline quality. When Mo doping content exceeds 3.93 Wt%, the ZnO films transform c-axis oriented into amorphous. The AFM pattern indicates that the surface of amorphous MZO film is extraordinarily flat. The Rq is 498 pm. The transmittance spectra reveal that all samples have an average transmittance of 80% in the visible light range. The optical band gap energy (Eg) increases from 3.28 to 3.60 eV as the Mo doping content increase. The absorbance spectrum indicates that ZnO surface plasmon resonance absorbance perk moves to short-wavelength as the Mo doping content increase. The Raman spectrum suggests that heavy Mo doping make the Raman scattering intensity decrease significantly. This paper obtains amorphous ZnO thin film by Mo doping. That broadens the application field of ZnO thin film materials. Meanwhile, we study the effect of Mo doping concentration on ZnO thin films surface plasmon, which provides important reference value for the preparation of oxidized zinc base photonic devices.

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