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1.
Toxicol Lett ; 349: 12-29, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34089816

RESUMO

The cholestatic liver injury could occur in response to a variety of diseases or xenobiotics. Although cholestasis primarily affects liver function, it has been well-known that other organs such as the kidney could be influenced in cholestatic patients. Severe cholestasis could lead to tissue fibrosis and organ failure. Unfortunately, there is no specific therapeutic option against cholestasis-induced organ injury. Hence, finding the mechanism of organ injury during cholestasis could lead to therapeutic options against this complication. The accumulation of potentially cytotoxic compounds such as hydrophobic bile acids is the most suspected mechanism involved in the pathogenesis of cholestasis-induced organ injury. A plethora of evidence indicates a role for the inflammatory response in the pathogenesis of several human diseases. Here, the role of nuclear factor-kB (NFkB)-mediated inflammatory response is investigated in an animal model of cholestasis. Bile duct ligated (BDL) animals were treated with sulfasalazine (SSLZ, 10 and 100 mg/kg, i.p) as a potent inhibitor of NFkB signaling. The NFkB proteins family activity in the liver and kidney, serum and tissue levels of pro-inflammatory cytokines, tissue biomarkers of oxidative stress, serum markers of organ injury, and the liver and kidney histopathological alterations and fibrotic changes. The oxidative stress-mediated inflammatory-related indices were monitored in the kidney and liver at scheduled time intervals (3, 7, and 14 days after BDL operation). Significant increase in serum and urine markers of organ injury, besides changes in biomarkers of oxidative stress and tissue histopathology, were evident in the liver and kidney of BDL animals. The activity of NFkB proteins (p65, p50, p52, c-Rel, and RelB) was significantly increased in the liver and kidney of cholestatic animals. Serum and tissue levels of pro-inflammatory cytokines (IL-1ß, IL-2, IL-6, IL-7, IL-12, IL-17, IL-18, IL-23, TNF-α, and INF-γ) were also higher than sham-operated animals. Moreover, TGF- ß, α-SMA, and tissue fibrosis (Trichrome stain) were evident in cholestatic animals' liver and kidneys. It was found that SSLZ (10 and 100 mg/kg/day, i.p) alleviated cholestasis-induced hepatic and renal injury. The effect of SSLZ on NFkB signaling and suppression of pro-inflammatory cytokines could play a significant role in its protective role in cholestasis. Based on these data, NFkB signaling could receive special attention to develop therapeutic options to blunt cholestasis-induced organ injury.


Assuntos
Anti-Inflamatórios/farmacologia , Colestase/tratamento farmacológico , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Nefropatias/prevenção & controle , Rim/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , NF-kappa B/antagonistas & inibidores , Sulfassalazina/farmacologia , Animais , Colestase/metabolismo , Colestase/patologia , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Regulação para Baixo , Rim/metabolismo , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Ligadura , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
2.
Transl Lung Cancer Res ; 9(5): 2016-2026, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33209621

RESUMO

Background: Lung nodules are a diagnostic challenge. Current clinical management of lung nodule patients is inefficient and therefore causes patient misclassification, which increases healthcare expenses. However, a precise and robust lung nodule classifier to minimize discomfort for patients and healthcare costs is still lacking. The aim of the present protocol is to evaluate the effectiveness of using a liquid biopsy classifier to diagnose nodules compared to physician estimates and whether the classifier can reduce the number of unnecessary biopsies in benign cases. Methods: A prospective cohort of 10,560 patients enrolled at 23 clinical centers in China with non-calcified pulmonary nodules, ranging from 0.5 to 3 cm in diameter, indicated by LDCT or CT will be included. After signed consent forms, the participants' pulmonary nodules will be assessed using three evaluation tools: (I) physician cancer probability estimates (II) validated lung nodule risk models, including Mayo Clinic and Veteran's Affairs models (III) ctDNA methylation classifier previously established. Each patient will undergo LDCT/CT follow-ups for 2 to 3 years and their information and one blood sample will be collected at baseline, 3, 6, 12, 24 and 36 months. The primary study outcomes will be the diagnostic accuracy of the methylation classifier in the cohort. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) will be used to compare the diagnostic value of each testing tool in differentiating benign and malignant pulmonary nodules. Discussion: We are conducting an observational study to explore the accuracy of using a ctDNA methylation classifier for incidental lung nodules diagnosis. Trial registration: Clinicaltrials.gov NCT03651986.

3.
J Craniofac Surg ; 30(7): 2174-2177, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31425405

RESUMO

BACKGROUND: Underdevelopment of nose and chin in East Asians is quite common. Rhinoplasty and mentoplasty are effective procedures to solve the above-depicted defects and can achieve remarkable cosmetic effects. An autologous costal cartilage graft has become an ideal material for rhinoplasty, especially for revision surgery. However, many problems in the clinical application of costal cartilage remain unresolved. This study is to investigate application strategies of autologous costal cartilage grafts in rhino- and mentoplasty. METHODS: The methods involved are as follows: application of an integrated cartilage scaffold; comprehensive application of diced cartilage; and chin augmentation of an autologous costal cartilage graft. RESULTS: In this study, satisfactory facial contour appearance was immediately achieved in 28 patients after surgery; 21 patients had satisfactory appearance of the nose and chin during the 6- to 18-month follow-up. Cartilage resorption was not observed. Two patients had nasal tip skin redness and were cured after treatment. CONCLUSION: This procedure can be used to effectively solve: curvature of the costal cartilage segment itself; warping of the carved costal cartilage; and effective use of the costal cartilage segment. The procedure has achieved satisfactory outcomes, and its application is worth extending to clinical practice.


Assuntos
Cartilagem Costal/transplante , Mentoplastia , Rinoplastia , Adolescente , Adulto , Autoenxertos/cirurgia , Queixo/cirurgia , Feminino , Humanos , Nariz/cirurgia , Adulto Jovem
4.
Environ Sci Technol ; 53(15): 8985-8993, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31189066

RESUMO

Hydrophobicity and molecular weight (MW) are two fundamental properties of dissolved organic matter (DOM) in wastewater treatment systems. This study proposes fluorescence Stokes shift and specific fluorescence intensity (SFI) as novel indicators of hydrophobicity and MW. These indicators originate from the energy gap and photon efficiency of the fluorescence process and can be readily extracted from a fluorescence excitation-emission matrix (EEM). The statistical linkages between these indicators and hydrophobicity/MW were explored through investigation of DOM across 10 full-scale membrane bioreactors treating municipal wastewater. Stokes shift was found to exhibit a general rule among the hydrophobicity components in the order of hydrophilic substances (HIS) < hydrophobic acids (HOA) < hydrophobic bases (HOB). The Stokes shift of 1.2 µm-1 is a critical border, above which the relative fluorescence correlated significantly with the HOA-related content (Pearson's r = 0.8). With regard to MW distribution (<1, 1-10, 10-100, and >100 kDa), SFI was found to be the most sensitive to the change of MW of <1 kDa proportion, especially at the excitation/emission wavelengths of 200-320/310-550 nm (r > 0.9). Hydrophobicity-related π conjugation and MW-dependent light exposure might be responsible for the correlations. These fluorescence indicators may be useful for convenient monitoring of DOM in wastewater treatment systems.


Assuntos
Poluentes Químicos da Água , Reatores Biológicos , Substâncias Húmicas , Interações Hidrofóbicas e Hidrofílicas , Peso Molecular , Espectrometria de Fluorescência , Águas Residuárias
5.
Cancer Sci ; 110(6): 2014-2021, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31033100

RESUMO

This study aimed to analyze the association between driver mutations and predictive markers for some anti-tumor agents in non-small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC-related driver genes. In addition, the slides were tested for PD-L1, excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and ß-tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild-type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild-type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower ß-tubulin III expression. In addition, wild-type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD-L1 high expression. As a pilot validation, 21 wild-type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo-regimen where targeted therapy has not been a routine option. Further validation is warranted.


Assuntos
Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/genética , Mutação , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Pemetrexede/administração & dosagem , Prognóstico , Taxoides/uso terapêutico
7.
Water Res ; 93: 205-213, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26905799

RESUMO

Reducing the energy consumption of membrane bioreactors (MBRs) is highly important for their wider application in wastewater treatment engineering. Of particular significance is reducing aeration in aerobic tanks to reduce the overall energy consumption. This study proposed an in situ ammonia-N-based feedback control strategy for aeration in aerobic tanks; this was tested via model simulation and through a large-scale (50,000 m(3)/d) engineering application. A full-scale MBR model was developed based on the activated sludge model (ASM) and was calibrated to the actual MBR. The aeration control strategy took the form of a two-step cascaded proportion-integration (PI) feedback algorithm. Algorithmic parameters were optimized via model simulation. The strategy achieved real-time adjustment of aeration amounts based on feedback from effluent quality (i.e., ammonia-N). The effectiveness of the strategy was evaluated through both the model platform and the full-scale engineering application. In the former, the aeration flow rate was reduced by 15-20%. In the engineering application, the aeration flow rate was reduced by 20%, and overall specific energy consumption correspondingly reduced by 4% to 0.45 kWh/m(3)-effluent, using the present practice of regulating the angle of guide vanes of fixed-frequency blowers. Potential energy savings are expected to be higher for MBRs with variable-frequency blowers. This study indicated that the ammonia-N-based aeration control strategy holds promise for application in full-scale MBRs.


Assuntos
Reatores Biológicos , Membranas Artificiais , Eliminação de Resíduos Líquidos/métodos , Purificação da Água/métodos , Ar , Algoritmos , Amônia/química , Amônia/metabolismo , Simulação por Computador , Engenharia/instrumentação , Engenharia/métodos , Modelos Teóricos , Oxigênio/metabolismo , Eliminação de Resíduos Líquidos/instrumentação , Purificação da Água/instrumentação
8.
Bioresour Technol ; 200: 328-34, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26512855

RESUMO

Geometry property would affect the hydrodynamics of membrane bioreactor (MBR), which was directly related to membrane fouling rate. The simulation of a bench-scale MBR by computational fluid dynamics (CFD) showed that the shear stress on membrane surface could be elevated by 74% if the membrane was sandwiched between two baffles (baffled MBR), compared with that without baffles (unbaffled MBR). The effects of horizontal geometry characteristics of a bench-scale membrane tank were discussed (riser length index Lr, downcomer length index Ld, tank width index Wt). Simulation results indicated that the average cross flow of the riser was negatively correlated to the ratio of riser and downcomer cross-sectional area. A relatively small tank width would also be preferable in promoting shear stress on membrane surface. The optimized MBR had a shear elevation of 21.3-91.4% compared with unbaffled MBR under same aeration intensity.


Assuntos
Reatores Biológicos , Hidrodinâmica , Membranas Artificiais , Purificação da Água/métodos , Simulação por Computador , Filtração , Microesferas , Modelos Teóricos , Poliestirenos/química , Reprodutibilidade dos Testes , Resistência ao Cisalhamento , Estresse Mecânico , Propriedades de Superfície , Águas Residuárias
9.
Vaccine ; 33(46): 6307-13, 2015 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-26432910

RESUMO

There is accumulating evidence that many invertebrates including insects can acquire enhanced immune protection against subsequently pathogens infection through immune priming. However, whether the toxin protein from pathogenic bacteria can induce such priming response remains unclear. Here we cloned, expressed and purified the toxin Photorhabdus insect-related proteins A2B2 (PirA2B2) from Photorhabdus luminescens TT01. We primed Galleria mellonella with sublethal dose of PirA2B2 and then challenged the larvae with viable P. luminescens TT01 at 48 h after priming. We found no evidence for immune priming in G. mellonella larvae exposed to PirA2B2. Priming the larvae with PirA2B2 did not improve their resistance in a subsequent challenge with P. luminescens TT01. Whereas a robust priming response was observed when the larvae exposed to lipopolysaccharide (LPS) extracted from P. luminescens TT01. Because the larvae primed with LPS showed significant higher resistance against P. luminescens TT01 infection than those of the PBS and BSA controls. Furthermore, we investigated the changes of the cellular immune parameters, such as hemocyte counts, phagocytic activity and encapsulation ability of the hemocytes, after priming. We found that the toxin PirA2B2 significantly decreased the cellular immunity of the larvae, whereas the LPS significantly increased them. These results indicated that the degree of priming response in G. mellonella correlated positively to the levels of cellular immune parameters, and the underlying mechanism in regulating the immune priming of invertebrates was not homologous to that of the immunological memory of vertebrates.


Assuntos
Toxinas Bacterianas/metabolismo , Imunossupressores/metabolismo , Lepidópteros/efeitos dos fármacos , Lepidópteros/imunologia , Photorhabdus/fisiologia , Animais , Toxinas Bacterianas/imunologia , Imunidade Celular/efeitos dos fármacos , Imunossupressores/imunologia , Larva/efeitos dos fármacos , Larva/imunologia , Lepidópteros/crescimento & desenvolvimento , Lepidópteros/microbiologia , Lipopolissacarídeos/imunologia , Photorhabdus/imunologia
10.
Acta Crystallogr D Biol Crystallogr ; 71(Pt 2): 185-95, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25664730

RESUMO

Lactate dehydrogenase (LDH) is an essential metabolic enzyme that catalyzes the interconversion of pyruvate and lactate using NADH/NAD(+) as a co-substrate. Many cancer cells exhibit a glycolytic phenotype known as the Warburg effect, in which elevated LDH levels enhance the conversion of glucose to lactate, making LDH an attractive therapeutic target for oncology. Two known inhibitors of the human muscle LDH isoform, LDHA, designated 1 and 2, were selected, and their IC50 values were determined to be 14.4 ± 3.77 and 2.20 ± 0.15 µM, respectively. The X-ray crystal structures of LDHA in complex with each inhibitor were determined; both inhibitors bind to a site overlapping with the NADH-binding site. Further, an apo LDHA crystal structure solved in a new space group is reported, as well as a complex with both NADH and the substrate analogue oxalate bound in seven of the eight molecules and an oxalate only bound in the eighth molecule in the asymmetric unit. In this latter structure, a kanamycin molecule is located in the inhibitor-binding site, thereby blocking NADH binding. These structures provide insights into LDHA enzyme mechanism and inhibition and a framework for structure-assisted drug design that may contribute to new cancer therapies.


Assuntos
L-Lactato Desidrogenase/antagonistas & inibidores , L-Lactato Desidrogenase/química , Neoplasias/enzimologia , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , L-Lactato Desidrogenase/metabolismo , Lactato Desidrogenase 5 , Simulação de Acoplamento Molecular , NAD/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Ácido Oxálico/metabolismo , Conformação Proteica
11.
Huan Jing Ke Xue ; 35(9): 3302-8, 2014 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-25518645

RESUMO

Catalytic oxidations of two-component volatile organic compounds (VOCs) toluene and chlorobenzene were investigated under microwave heating and tube furnace heating, respectively, and reaction kinetics were analyzed in this paper. The research indicated that competitive adsorption between toluene and chlorobenzene reduced their removal efficiencies by 3% -12% as compared to single component. 'Hot spot effect' and 'non-thermal effect' under microwave irradiation obviously enhanced conversion efficiencies of VOCs, especially, the chlorobenzene removal was increased by 31% -38%. Moreover, reaction temperature and energy consumption were both reduced under microwave heating. The dynamic calculations showed that microwave heating decreased the activation energies by 2 146 J. mol-1 and 1 450 J mol-1 for toluene and chlorobenzene, respectively, as compared with tube furnace heating. Meanwhile, microwave heating enhanced the reaction rate constants of chlorobenzene and toluene to about 35 times and 6 times of that of tube furnace heating.


Assuntos
Clorobenzenos/química , Tolueno/química , Compostos Orgânicos Voláteis/química , Adsorção , Catálise , Temperatura Alta , Cinética , Micro-Ondas , Oxirredução , Temperatura
12.
J Med Chem ; 57(5): 2033-46, 2014 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-24320933

RESUMO

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Sequência de Bases , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Primers do DNA , Método Duplo-Cego , Fluorenos/farmacocinética , Fluorenos/farmacologia , Meia-Vida , Humanos , Macaca fascicularis , Masculino , Placebos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
13.
PLoS One ; 8(10): e77398, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24143229

RESUMO

BACKGROUND: Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is crucial for successful drug development. However, due to immune tolerance, making it difficult to generate antibodies using conventional approaches. METHODOLOGY/FINDINGS: Mixed four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; sixteen highly positive hybridoma colonies were selected via fluorescence-activated cell sorting-high throughput screening (FACS-HTS) using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus human PBMC controls). MS17-57 and control commercial Alkaline Phosphatase (ALP) mAbs were used to confirm the target antigens (Ags), which were identified as ALPs expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). MS identified the Ags recognized by MS17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules. Immunofluorescence staining using MS17-57 demonstrated higher staining of gastrointestinal (GI) cancer tissues compared to normal GI tissues (P<0.03), and confirmed binding of MS17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assays using the PALP/IALP-expressing GC cell lines demonstrated that MS17-57 inhibited cell growth by 32 ± 8%. Transwell cell migration assays documented that MS17-57 can inhibit PALP/IALP-expressing GI cancer cell migration by 25 ± 5%. MS17-57 mAb inhibited tumor growth in nude mice. CONCLUSIONS: Our findings indicate that PALP and IALP can be ectopically expressed on extracellular matrix of GI cancers, and that MS17-57 directed against PALP/IALP can inhibit GI cancer cells growth and migration in vitro and in vivo. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.


Assuntos
Fosfatase Alcalina/genética , Fosfatase Alcalina/imunologia , Anticorpos Monoclonais/imunologia , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Regulação Neoplásica da Expressão Gênica , Terapia de Alvo Molecular/métodos , Fosfatase Alcalina/metabolismo , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/genética , Anticorpos Monoclonais/uso terapêutico , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Transformação Celular Neoplásica , Neoplasias Gastrointestinais/genética , Humanos , Espaço Intracelular/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Transdução de Sinais
14.
Huan Jing Ke Xue ; 34(6): 2107-15, 2013 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-23947020

RESUMO

Molecular sieve loaded catalyst was prepared by impregnation method, microwave-absorbing material silicon carbide and the catalyst were investigated for catalytic oxidation of toluene by microwave irradiation. Research work examined effects of silicon carbide and molecular sieve loading Cu-V catalyst's mixture ratio as well as mixed approach changes on degradation of toluene, and characteristics of catalyst were measured through scanning electron microscope, specific surface area test and X-ray diffraction analysis. The result showed that the fixed bed reactor had advantages of both thermal storage property and low-temperature catalytic oxidation when 20% silicon carbide was filled at the bottom of the reactor, and this could effectively improve the utilization of microwave energy as well as catalytic oxidation efficiency of toluene. Under microwave power of 75 W and 47 W, complete-combustion temperatures of molecular sieve loaded Cu-V catalyst and Cu-V-Ce catalyst to toluene were 325 degrees C and 160 degrees C, respectively. Characteristics of the catalysts showed that mixture of rare-earth element Ce increased the dispersion of active components in the surface of catalyst, micropore structure of catalyst effectively guaranteed high adsorption capacity for toluene, while amorphous phase of Cu and V oxides increased the activity of catalyst greatly.


Assuntos
Poluentes Atmosféricos/isolamento & purificação , Poluição do Ar/prevenção & controle , Compostos Inorgânicos de Carbono/química , Compostos de Silício/química , Tolueno/isolamento & purificação , Poluentes Atmosféricos/química , Catálise , Cromatografia em Gel , Micro-Ondas , Oxirredução , Tolueno/química
15.
Wei Sheng Wu Xue Bao ; 52(4): 532-7, 2012 Apr 04.
Artigo em Chinês | MEDLINE | ID: mdl-22799220

RESUMO

OBJECTIVE: The predicted amino acid sequence of locus plu4437-plu4436 in the genome of Photorhabdus luminescens TT01 (referred to as pirA2B2) has a consistency of 50% and 45% with locus plu4093-plu4092 (referred to as pirA1B1) , respectively. PirA1B1 has been confirmed with oral insecticidal activity against Plutella xylostella and mosquito. The purpose of the present study was to examine whether pirA2B2 possesses insecticidal activity. METHODS: pirA2, pirB2 and pirA2B2 genes were PCR amplified and cloned. The recombinant expression vector pQE-pirA2, pQE-pirB2 and pQE-pirA2B2 were constructed and transferred into E. coli M15, individually. The soluble PirA2, PirB2 and PirA2B2 proteins were detected from the supernatant of the recombinant M15 induced with IPTG by both SDS-PAGE and Western-blot. The proteins expressed in the three recombinant E. coli M15 strains were purified by affinity chromatography combined with desalination technology and then quantified individually. The heamocoal and oral insecticidal activities of the expressed proteins were analyzed against the larvae of Galleria mellonella and Spodoptera litura. RESULTS: The results show: 1. PirA2B2 had heamocoal insecticidal activity against the fifth instar larvae of both G. mellonella and S. litura, with an LD50 of 4.0 and 2.8 microg/larvae, respectively, 2. neither PirA2 nor PirB2 alone had heamocoal insecticidal activity against the insects tested, while the mixture of PirA2 and PirB2 reconstituted full activity, and 3. PirA2B2 showed no oral insecticidal activity to the first instar larvae of either G. mellonella or S. litura. CONCLUSION: pirA2B2 in the genome of P. luminescens TT01 is a binary insecticidal toxin gene. SIGNIFICANCE: The successful expression and purifcation of PirA2B2 laid a foundation for further study on the function, insecticidal mechanism and expression regulation of the binary toxins.


Assuntos
Regulação Bacteriana da Expressão Gênica , Genes Bacterianos , Inseticidas/metabolismo , Photorhabdus/genética , Animais , Clonagem Molecular , Inseticidas/farmacologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/farmacologia , Spodoptera
16.
Bioorg Med Chem Lett ; 22(15): 5108-13, 2012 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-22749870

RESUMO

Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.


Assuntos
Proteínas de Transporte de Cátions/antagonistas & inibidores , Tioureia/química , Animais , Células CACO-2 , Proteínas de Transporte de Cátions/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/patologia , Ratos , Relação Estrutura-Atividade , Tioureia/síntese química , Tioureia/farmacologia
17.
Bioorg Med Chem Lett ; 21(12): 3676-81, 2011 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-21570288

RESUMO

Starting from the oxindole 2a identified through a high-throughput screening campaign, a series of Na(V)1.7 blockers were developed. Following the elimination of undesirable structural features, preliminary optimization of the oxindole C-3 and N-1 substituents afforded the simplified analogue 9b, which demonstrated a 10-fold increase in target potency versus the original HTS hit. A scaffold rigidification strategy then led to the discovery of XEN907, a novel spirooxindole Na(V)1.7 blocker. This lead compound, which in turn showed a further 10-fold increase in potency, represents a promising structure for further optimization efforts.


Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Dor , Canais de Sódio/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Analgésicos/química , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Indóis/química , Concentração Inibidora 50 , Estrutura Molecular , Canal de Sódio Disparado por Voltagem NAV1.7 , Oxindóis , Compostos de Espiro/química , Relação Estrutura-Atividade
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