RESUMO
A Gram-stain-negative, aerobic, rod-shaped, non-flagellated, non-gliding bacterial strain, designated MT50T, was isolated from a deep-sea sediment sample collected from the Mariana Trench. Optimal growth of strain MT50T was observed at 25â°C, pH 7.0-7.5 and in the presence of 3-5â% (w/v) NaCl. The strain was positive for oxidase and catalase. Phylogenetic analysis of 16S rRNA gene sequences revealed that strain MT50T is affiliated with the genus Mesonia, showing the highest sequence similarity (98.5â%) to the type strain of Mesonia ostreae. The digital DNA-DNA hybridization and average nucleotide identity values between strain MT50T and four closely related type strains of known Mesonia species (14.1-54.8 % and 72.7-86.8â%, respectively) were all below the threshold values to discriminate bacterial species, indicating that strain MT50T is affiliated with a novel species within the genus. The genomic G+C content deduced from the genome of strain MT50T was 36.2 mol%. The major fatty acids of strain MT50T were iso-C15â:â0, iso-C17â:â0 3-OH and anteiso-C15â:â0. The predominant respiratory quinone of the strain was MK-6. The polar lipids of strain MT50T included phosphatidylethanolamine and two unidentified lipids. Based on the polyphasic data presented in this study, strain MT50T represents a novel species of the genus Mesonia, for which the name Mesonia profundi sp. nov. is proposed. The type strain is MT50T (=MCCC 1K07833T=KCTC 92380T).
Assuntos
Ácidos Graxos , Filogenia , RNA Ribossômico 16S/genética , Composição de Bases , Ácidos Graxos/química , Análise de Sequência de DNA , DNA Bacteriano/genética , Técnicas de Tipagem BacterianaRESUMO
A series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos , Animais , Humanos , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Camundongos Nus , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Proliferação de Células , Inibidores de Proteínas Quinases/química , Antineoplásicos/química , Linhagem Celular TumoralRESUMO
MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.
Assuntos
Antineoplásicos/farmacologia , Enzimas Reparadoras do DNA/antagonistas & inibidores , Diaminas/farmacologia , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/farmacologia , Ensaios de Triagem em Larga Escala , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Enzimas Reparadoras do DNA/metabolismo , Diaminas/síntese química , Diaminas/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Monoéster Fosfórico Hidrolases/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , TermodinâmicaRESUMO
HDAC6 receives great attention because of its therapeutic potential for the treatment of various diseases. Selective fluorescence imaging for HDAC6 is important for its pathological and biological studies. However, specific detection of HDAC6 by using a fluorescent small molecule probe remains a great challenge. Herein, a series of fluorescent HDAC6-selective inhibitors incorporating a naphthalimide skeleton were designed and synthesized. A structure-activity relationship study identified that compound JW-1 had the greatest inhibitory activity and superior specificity against HDAC6. JW-1 could substantially increase α-tubulin acetylation and was active against a panel of six cancer cell lines. Photophysical characterization and cellular imaging of MDA-MB-231 cells demonstrated that JW-1 is a highly fluorescent, cell penetrable, small-molecule inhibitor of HDAC6 that can be used for the detection of HDAC6 in complex cellular environments.
Assuntos
Corantes Fluorescentes/química , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Linhagem Celular Tumoral , Corantes Fluorescentes/síntese química , Inibidores de Histona Desacetilases/síntese química , Humanos , Simulação de Acoplamento Molecular , Imagem Óptica , Relação Estrutura-AtividadeRESUMO
PURPOSE: The purpose of this study was to analyze the biomechanical effects of four different designs of frog appliances for molar distalization using finite element analysis. METHODS: A three-dimensional finite element model including complete dentition, periodontal ligament, palatine, and alveolar bone was established. Four types of frog appliances were designed to simulate maxillary molar distalization: tooth-button-borne (Type A), bone-borne (Type B), bone-button-borne (Type C), and tooth-bone-borne (Type D) frog appliances. A force of 10â¯N was applied simulating a screw in the anteroposterior direction. To assess the von Mises stress distribution and the resultant displacements in the teeth and periodontal tissues, geometric nonlinear theory was utilized. RESULTS: Compared to the conventional tooth-borne frog appliance (Type A), the bone-borne frog appliances showed increased first molar distalization with enhanced mesiolingual rotation and distal tipping, but the labial inclination and intrusion of the incisors were insignificant. When replacing the palatal acrylic button with miniscrews (Types B and D), more anchorage forces were transmitted from the first premolar to palatine bone, which was further dispersed by the assistance of a palatal acrylic button (Type C). CONCLUSIONS: Compared to tooth-borne frog appliances, the bone-borne variants demonstrated a clear advantage for en masse molar distalization. The combined anchorage system utilizing palatal acrylic buttons and miniscrews (Type C) offers the most efficient stress distribution, minimizing force concentration on the palatine bone.
RESUMO
OBJECTIVE: To evaluate the impact of insulin resistance (IR) on prognosis in non-diabetic acute coronary syndrome patients. METHODS: In this prospective study, we enrolled 332 non-diabetic patients suffering from acute coronary syndrome. The patients were divided into three groups by HOMA-IR which calculated by formula: low HOMA-IR group (HOMA-IR < 2), 44 cases; moderate HOMA-IR group (2 ≤ HOMA2-IR < 6), 99 cases; high HOMA-IR group (HOMA ≥ 6) with HOMA index, 179 cases. The in-hospital medical records of patients were compared, and all patients were followed up for one year after discharge. RESULTS: Incidence of hypertension (P = 0.013), dyslipidemia (P < 0.001), faster resting heart rate (P < 0.001) and number of triple vessel coronary artery disease (P = 0.017) in high HOMA-IR group were significantly higher than in low and moderate HOMA-IR group. During follow-up, the major end-point events increased in proportion to IR grade: 64.3% (26/44) in the high HOMA-IR group, 54.7% (52/99) in moderate HOMA-IR group and 41.3% (74/199) in low HOMA-IR group (P = 0.034). Multivariable logistic regression analysis showed that high sensitivity C reactive protein (OR = 1.012, 95%CI:1.002-1.022, P = 0.022), HOMA-IR (OR = 1.250, 95%CI:1.043-1.497, P = 0.015) , triple vessel coronary artery disease (OR = 5.914, 95%CI:2.947-11.868, P < 0.001) , ischemic changes on ECG (OR = 5.495, 95%CI:2.925-10.324, P < 0.001) and low left ventricular ejection fraction (LVEF ≤ 40%) (OR = 13.205, 95%CI:5.000-34.661, P < 0.001) were independent risk factor for major end-point events during follow-up. CONCLUSIONS: Increased insulin resistance is linked with poor prognosis of non-diabetic patients with acute coronary syndrome.
Assuntos
Síndrome Coronariana Aguda , Resistência à Insulina , Idoso , Feminino , Seguimentos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos ProspectivosRESUMO
Rare earth elements (REEs) are widely used in optoelectronic industries, and they can be emitted into the environment and may induce biological effects. In this study, we investigated the provenance and bioaccessibility of REEs in atmospheric particles (APs) collected from areas impacted by the optoelectronic industry. The geoaccumulation index (Igeo) values showed that Y, Eu, and Tb were much more enriched in the APs from the optoelectronic recycling sites than in those from the optoelectronic producing sites and were not enriched in the APs from the optoelectronic administrative sites and background sites. The characteristic parameters and the distribution patterns of REEs demonstrated that the AP samples from the recycling sites and producing sites showed remarkably positive Eu and Tb anomalies. According to the positive matrix factorization (PMF) model, the optoelectronic industry was quantitatively determined to contribute 82.8% of Y, 86.5% of Eu, and 83.4% of Tb. Furthermore, an in vitro physiologically based extraction test (PBET) was performed to assess the bioaccessibility of REEs in the APs. The results showed that the bioaccessibility of all the REEs in the APs was below 50.0% in the human gastrointestinal tract, with higher values in the gastric phases than in the intestinal phases. In particular, extremely low gastric bioaccessibilities of Tb and Ce and relatively high gastric bioaccessibilities of Y and Eu were observed in the APs from the recycling sites and producing sites, which may due to the chemical composition of the compounds containing REEs that are used in the optoelectronic industry. In conclusion, our results provide additional information about the contribution and influence of the optoelectronic industry on the provenance and bioaccessibility of REEs in APs.
Assuntos
Metais Terras Raras , HumanosRESUMO
We demonstrate that the acrylamide group can be used to improve the drug-like properties of potential drug candidates. In the EGFR inhibitor development, both the solubility and membrane permeability properties of compounds 6a and 7, each containing an acrylamide group, were substantially better than those of gefitinib (1) and AZD3759 (2), respectively. We demonstrated that incorporation of an acrylamide moiety could serve as a good strategy for improving drug-like properties.
RESUMO
Glioblastoma is the most fatal type of primary brain cancer, and current treatments for glioblastoma are insufficient. HDAC6 is overexpressed in glioblastoma, and siRNA-mediated knockdown of HDAC6 inhibits glioma cell proliferation. Herein, we report a high-selective HDAC6 inhibitor, J22352, which has PROTAC (proteolysis-targeting chimeras)-like property resulted in both p62 accumulation and proteasomal degradation, leading to proteolysis of aberrantly overexpressed HDAC6 in glioblastoma. The consequences of decreased HDAC6 expression in response to J22352 decreased cell migration, increased autophagic cancer cell death and significant tumor growth inhibition. Notably, J22352 reduced the immunosuppressive activity of PD-L1, leading to the restoration of host anti-tumor activity. These results demonstrate that J22352 promotes HDAC6 degradation and induces anticancer effects by inhibiting autophagy and eliciting the antitumor immune response in glioblastoma. Therefore, this highly selective HDAC6 inhibitor can be considered a potential therapeutic for the treatment of glioblastoma and other cancers.
Assuntos
Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/síntese química , Neoplasias Experimentais/tratamento farmacológico , Quinazolinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Autofagia , Linhagem Celular Tumoral , Sobrevivência Celular , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Humanos , Masculino , Camundongos , Camundongos Nus , Estrutura Molecular , Quinazolinas/química , Quinazolinas/farmacologiaRESUMO
Bioisosteric replacement of acylureido moiety in 6-acylureido-3-pyrrolylmethylidene-2-oxoindoline derivatives resulted in a series of malonamido derivatives with indolin-2-one scaffold (11-14). Further conformational restrictions of the malonamido moiety led to 2-oxo-1,2-dihydropyridine (21-25) or a 4-oxo-1,4-dihydropyridine derivatives (31-36). 4-Oxo-1,4-dihydropyridine derivatives were more potent Aurora B inhibitors than their 2-oxo-1,2-dihydropyridine counterparts and demonstrated cytotoxicities against A549 and HepG2 cells in the submicromolar range. In A549 cells, 31h decreased phosphorylation of histone H3, triggered polyploidy, induced expression of pro-apoptotic Fas and FasL with subsequent activation of caspase 8, resulting into apoptosis. In a Huh7-xenograft mouse model, 31h demonstrated potent in vivo efficacy with a daily dose of 5 mg/kg.
Assuntos
Antineoplásicos/farmacologia , Aurora Quinase B/antagonistas & inibidores , Di-Hidropiridinas/farmacologia , Inibidores Enzimáticos/farmacologia , Indóis/química , Piridonas/química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Aurora Quinase B/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Malonatos/química , Estrutura Molecular , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/química , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A series of 6-acylureido derivatives containing a 3-(pyrrol-2-ylmethylidene)indolin-2-one scaffold were synthesized as potential dual Aurora B/FLT3 inhibitors by replacing the 6-arylureido moiety in 6-arylureidoindolin-2-one-based multi-kinase inhibitors. (Z)-N-(2-(pyrrolidin-1-yl)ethyl)-5-((6-(3-(2-fluoro-4-methoxybenzoyl)ureido)-2-oxoindolin-3-ylidene)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamide (54) was identified as a dual Aurora B/FLT3 inhibitor (IC50 = 0.4 nM and 0.5 nM, respectively). Compound 54 also exhibited potent cytotoxicity with single-digit nanomolar IC50 values against the FLT3 mutant-associated human acute myeloid leukemia (AML) cell lines MV4-11 (FLT3-ITD) and MOLM-13 (FLT3-ITD). Compound 54 also specifically induced extrinsic apoptosis by inhibiting the phosphorylation of the Aurora B and FLT3 pathways in MOLM-13 cells. Compound 54 had a moderate pharmacokinetic profile. The mesylate salt of 54 efficiently inhibited tumor growth and reduced the mortality of BALB/c nude mice (subcutaneous xenograft model) that had been implanted with AML MOLM-13 cells. Compound 54 is more potent than sunitinib not only against FLT3-WT AML cells but also active against sunitinib-resistant FLT3-ITD AML cells. This study demonstrates the significance of dual Aurora B/FLT3 inhibitors for the development of potential agents to treat AML.
Assuntos
Aurora Quinase B/antagonistas & inibidores , Desenho de Fármacos , Indóis/química , Indóis/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Chlorocebus aethiops , Humanos , Indóis/síntese química , Indóis/uso terapêutico , Masculino , Camundongos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Células Vero , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
PURPOSE: The purpose of this study was to compare the salivary immunoglobulin A antibody response to Streptococcus mutans in normal with in heat treated stress. METHODS: Clinical Streptococcus mutans strains were isolated from 20 volunteers, serotyped by biochemical test and PCR, and genotyped by AP-PCR. Unstimulated secretions from submandibular glands and sublingual glands were collected from volunteers by modified collectors. Each identified genotype was cultured in two groups: control group was grown in BHI broth at 37 degrees C. for 3 hours; stress group was incubated in BHI broth at 42 degrees C. for 3 hours. Analysis of SIgA activity to clinical genotype strains and reference strains in different group was detected by Western blot. RESULTS: There was no significant difference between stress group and control group,in spite that some bands had strong or weak intensity. Different genotypes of S.mutans could have different immunoblotting profile as for an individual. SIgA from different volunteers could have different immonoblotting profiles as to the same genotype strain. CONCLUSIONS: Although Streptococcus mutans can express heat shock proteins in stress, this study suggests these new proteins have no significant effect on the reaction of SIgA to Streptococcus mutans. Different genotype strains may have different proteins, and different immunoreactivity to host. Different hosts may have different immunoreactivities to one genotypes of S.mutans.
Assuntos
Resposta ao Choque Térmico , Imunoglobulina A Secretora/imunologia , Saliva/imunologia , Streptococcus mutans/imunologia , Western Blotting , Temperatura Alta , Humanos , Imunoglobulina A/imunologiaRESUMO
OBJECTIVE: To test the salivary immunoglobulin A antibody activity to Streptococcus mutans in normal with in acid environment. METHODS: Streptococcus mutans strains were isolated from 20 volunteers, serotyped by biochemical test and PCR, and genotyped by AP-PCR. Unstimulated secretions from submandibular glands and sublingual glands were collected from volunteers by modified collectors. Each identified Streptococcus mutans genotype was cultured in two groups: control group was cultured in BHI broth pH7.2 at 37 degrees C for 2 h; acid shock group were cultured in TYEG broth (pH5.5) at 37 degrees C for 2 h. Analysis of SIgA activity to Streptococcus mutans genotypes in different groups was detected by Western blot. RESULTS: (1) The SIgA of each individual could response to his own Streptococcus mutans strains and the reference strains; (2) The same individual had different SIgA activity to different genotype strains; (3) There were no significant difference between acid groups and control groups, in spite that some bands had strong or weak intensity. CONCLUSIONS: Although Streptococcus mutans could express acid shock proteins in stress, the present study suggests that these new proteins have no qualitative effect on the reaction of SIgA to Streptococcus mutans.