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1.
Nat Commun ; 13(1): 621, 2022 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-35110538

RESUMO

The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). AT-527 recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, AT-527 is converted into its triphosphate form, AT-9010, that presumably targets the viral RNA-dependent RNA polymerase (RdRp, nsp12), for incorporation into viral RNA. Here we report a 2.98 Å cryo-EM structure of the SARS-CoV-2 nsp12-nsp7-nsp82-RNA complex, showing AT-9010 bound at three sites of nsp12. In the RdRp active-site, one AT-9010 is incorporated at the 3' end of the RNA product strand. Its modified ribose group (2'-fluoro, 2'-methyl) prevents correct alignment of the incoming NTP, in this case a second AT-9010, causing immediate termination of RNA synthesis. The third AT-9010 is bound to the N-terminal domain of nsp12 - known as the NiRAN. In contrast to native NTPs, AT-9010 is in a flipped orientation in the active-site, with its guanine base unexpectedly occupying a previously unnoticed cavity. AT-9010 outcompetes all native nucleotides for NiRAN binding, inhibiting its nucleotidyltransferase activity. The dual mechanism of action of AT-527 at both RdRp and NiRAN active sites represents a promising research avenue against COVID-19.


Assuntos
Antivirais/química , Antivirais/farmacologia , Guanosina Monofosfato/análogos & derivados , Fosforamidas/química , Fosforamidas/farmacologia , RNA Polimerase Dependente de RNA/antagonistas & inibidores , SARS-CoV-2/enzimologia , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , COVID-19/virologia , Microscopia Crioeletrônica , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Guanosina Monofosfato/química , Guanosina Monofosfato/farmacologia , Humanos , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , RNA Polimerase Dependente de RNA/metabolismo , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Proteínas Virais/genética
2.
Photosynth Res ; 152(1): 13-22, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34988868

RESUMO

Chlorophyll f is a new type of chlorophyll isolated from cyanobacteria. The absorption and fluorescence characteristics of chlorophyll f permit these oxygenic-photosynthetic organisms to thrive in environments where white light is scarce but far-red light is abundant. To explore the ligand properties of chlorophyll f and its energy transfer profiles we established two different in vitro reconstitution systems. The reconstituted peridinin-chlorophyll f protein complex (chlorophyll f-PCP) showed a stoichiometry ratio of 4:1 between peridinin and chlorophyll f, consistent with the peridinin:chlorophyll a ratio from native PCP complexes. Using emission wavelength at 712 nm, the excitation fluorescence featured a broad peak at 453 nm and a shoulder at 511 nm confirming energy transfer from peridinin to chlorophyll f. In addition, by using a synthetic peptide mimicking the first transmembrane helix of light-harvesting chlorophyll proteins of plants, we report that chlorophyll f, similarly to chlorophyll b, did not interact with the peptide contrarily to chlorophyll a, confirming the accessory role of chlorophyll f in photosystems. The binding of chlorophyll f, even in the presence of chlorophylls a and b, by PCP complexes shows the flexibility of chlorophyll-protein complexes and provides an opportunity for the introduction of new chlorophyll species to extend the photosynthetic spectral range.


Assuntos
Dinoflagelados , Clorofila/análogos & derivados , Clorofila/metabolismo , Clorofila A/metabolismo , Dinoflagelados/metabolismo , Guanosina Monofosfato/análogos & derivados , Fosforamidas
3.
J Hazard Mater ; 426: 127841, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-34844804

RESUMO

The microbial degradation of acephate in pure cultures has been thoroughly explored, but synergistic metabolism at the community level has rarely been investigated. Here, we report a novel microbial consortium, ZQ01, capable of effectively degrading acephate and its toxic product methamidophos, which can use acephate as a source of carbon, phosphorus and nitrogen. The degradation conditions with consortium ZQ01 were optimized using response surface methodology at a temperature of 34.1 °C, a pH of 8.9, and an inoculum size of 2.4 × 108 CFU·mL-1, with 89.5% of 200 mg L-1 acephate degradation observed within 32 h. According to the main products methamidophos, acetamide and acetic acid, a novel degradation pathway for acephate was proposed to include hydrolysis and oxidation as the main pathways of acephate degradation. Moreover, the bioaugmentation of acephate-contaminated soils with consortium ZQ01 significantly enhanced the removal rate of acephate. The results of the present work demonstrate the potential of microbial consortium ZQ01 to degrade acephate in water and soil environments, with a different and complementary acephate degradation pathway.


Assuntos
Consórcios Microbianos , Fosforamidas , Biodegradação Ambiental , Compostos Organotiofosforados , Solo , Microbiologia do Solo
4.
Environ Sci Pollut Res Int ; 29(4): 5923-5930, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34435288

RESUMO

There exists a visible evidence of linkage between pollutant exposure and nutritional deficiency in many organisms. The aim of the present study was to analyze the proximate composition of juvenile African catfish (Clarias gariepinus) exposed to polydimethylsiloxane (antifoam) for 56 days using a renewal bioassay. The moisture, crude protein, ash, and fat content of the fish samples were analyzed using standard methods. Antifoam concentrations at 0.0mg/L, 63.96mg/L, 127.9mg/L, 255.82mg/L, and 511.64mg/L were used for the sublethal exposure after which the proximate composition was analyzed. The water quality variables including dissolved oxygen, conductivity, and total dissolved solids varied as the concentration increased. The moisture and lipid contents were highest at 511.64mg/L concentration while the control(0.0mg/L) had the highest percentage composition of ash, protein, carbohydrate, and fiber contents which were normal values. The differences in proximate values were slightly significant at P>0.05 among the different concentrations. The findings in this study may be an indication that antifoam can significantly affect some water quality variables and proximate composition, while also portraying the risk associated with the consumption of such exposed fish.


Assuntos
Peixes-Gato , Poluentes Químicos da Água , Animais , Dimetilpolisiloxanos , Guanosina Monofosfato/análogos & derivados , Fosforamidas
5.
Sci Total Environ ; 806(Pt 4): 150863, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-34626633

RESUMO

Enantioselective metabolism of chiral pesticide in plants is very important. In vitro system has become an effective means to study the metabolism of pesticides in plants, but the study on the metabolism of chiral pesticides has not been reported. This work compared the enantiomer metabolic behavior of acephate and its metabolite methamidophos between tea cell suspensions and excised tea stem with leaves. (±)-Acephate could be absorbed and transferred well to top leaves by the cut end of excised stem after 24 h. (±)-Methamidophos was derived from the metabolism of (±)-acephate in tea plants at 3-5% in leaves and 2-3% in stems at 216 h. The content of (+)-methamidophos was 1.5 times higher than that of (-)-methamidophos in excised leaves. Though both (±)-acephate and (±)-methamidophos could be metabolized well by cell suspension, (±)-acephate and (±)-methamidophos was non-enantioselectively metabolized in cell suspension. It was shown that using the excised tea stem with leaves for chiral pesticide metabolism studies was much closer to intact plant than cell suspensions. This result also established an effective and easily available in vitro metabolic model for the study of enantioselective metabolism of chiral contaminants from environment.


Assuntos
Camellia sinensis , Inseticidas , Inseticidas/análise , Compostos Organotiofosforados , Fosforamidas , Folhas de Planta/química , Estereoisomerismo , Suspensões , Chá
6.
Phys Med Biol ; 66(22)2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34644694

RESUMO

Objective.Time-of-flight (TOF) and depth-of-interaction (DOI) are well recognized as important information to improve PET image quality. Since such information types are not correlated, many TOF-DOI detectors have been developed but there are only a few reports of high-resolution detectors (e.g. 1.5 mm resolution) for brain PET systems. Based on the DOI detector, which enables single-ended readout by optically coupling a pair of crystals and having a loop structure, we have developed the crosshair light sharing (CLS) PET detector that optically couples the four-loop structure, consisting of quadrisected crystals comparable in size to a photo-sensor, to four photo-sensors in close proximity arranged in a windmill shape. Even as a high-resolution detector, the CLS PET detector could obtain both TOF and DOI information. The coincidence resolving time (CRT) of the CLS PET detector needs to be further improved, however, for application to the brain PET system. Recently, a fast LGSO crystal was developed which has advantages in detection efficiency and CRT compared to the GFAG crystal. In this work, we developed the CLS PET detector using the fast LGSO crystal for the TOF-DOI brain PET system.Approach.The crystals were each 1.45 × 1.45 × 15 mm3and all surfaces were chemically etched. The CLS PET detector consisted of a 14 × 14 crystal array optically coupled to an 8 × 8 MPPC array.Main results.The fast LGSO array provided 10.1% energy resolution at 511 keV, 4.7 mm DOI resolution at 662 keV, and 293 ps CRT with the energy window of 440-620 keV.Significance.The developed CLS PET detector has 290% higher coincidence sensitivity, 30% better energy resolution, and 32% better time resolution compared to our previous CLS PET detector.


Assuntos
Encéfalo , Tomografia por Emissão de Pósitrons , Guanosina Monofosfato/análogos & derivados , Cabeça , Fosforamidas , Tomografia por Emissão de Pósitrons/métodos
7.
Bioorg Chem ; 115: 105193, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34339976

RESUMO

In this study, four novel phosphoramide ligands (L1-L4) are synthesized and characterized by 31PNMR, 1HNMR, MASS, and FT-IR spectroscopies. In vitro cell growth inhibition is studied by the MTT assay to evaluate the cytotoxicity of ligands against MCF-7 cell line; the result of the assay demonstrates that all ligands significantly suppress the proliferation of breast cancer cells in a concentration-dependent manner. The calculated IC50 values are in the range of 3.6-10.77 µg ml-1, of which the lowest value is attributed to L1. Then a facile approach was developed to functionalize graphene oxide (GO) surface by L1. The data which are obtained by XRD, FT-IR, and EDX analysis confirmed the deposition of phosphoramide on the surface of GO. The cell viability of GO-L1 compound at different concentrations is investigated in 24 h experiment. Excellent synergistic antitumor effects of GO and L1 lead to a decrease in IC50 value up to 2.13 µg ml-1. The Quantum calculations of compounds are used to study energies and HOMO and LUMO values, dipole moments (µ), global hardness (η), global softness (σ), and electrophilicity index (ω) using DMol3 module in Material studio2017. The docking calculations are performed to describe the mode of the binding to DNA and DNA polymerase IIα. Adsorption calculations of ligands (L1-L4) on GO sheet in the presence of water showed that L1 and L2 were located on GO via π electrons of anisole ring. While, L3 and L4 were located on GO by π - π interactions of aniline ring.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Grafite/química , Grafite/farmacologia , Fosforamidas/análogos & derivados , Fosforamidas/farmacologia , Antineoplásicos/síntese química , Sobrevivência Celular/efeitos dos fármacos , Grafite/síntese química , Humanos , Ligantes , Células MCF-7 , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Fosforamidas/síntese química
8.
Nucleic Acids Res ; 49(16): 9026-9041, 2021 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-34417625

RESUMO

The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect.


Assuntos
Oligonucleotídeos Antissenso/síntese química , Índice Terapêutico do Medicamento , Animais , Células HEK293 , Células HeLa , Humanos , Fígado/metabolismo , Masculino , Mesilatos/química , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Oligonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos Antissenso/toxicidade , Fosforamidas/química , Ligação Proteica , Distribuição Tecidual
9.
J UOEH ; 43(2): 197-203, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34092764

RESUMO

We gave mice a 540 mg/kg dose of LD50 acephate, followed by an assessment of acephate, methamidophos (MP), and choline esterase (ChE) activity for up to 4 hours (hr) in order to investigate the time course of acephate intoxication. At 1 hr, the blood acephate and MP levels were 428 ± 90 µg/ml (mean ± SEM) and 4.2 ± 0.4 µg/ ml, respectively. The liver acephate levels were similar to those in the blood, but the liver MP levels were approximately 3.5 times that of the blood at 1 hr. The brain MP level tended to be higher than the blood MP at 1 hr. These levels decreased gradually over 4 hr, but the brain acephate and MP levels surpassed the blood levels significantly at 4 hr, and after 2 hr, respectively. Serum, liver, cerebrum, cerebellum, and brainstem cholinesterase activity (ChE) were inhibited at 1 hr, and remained inhibited in all but the cerebellum until the end of the experiment. The obtained data were applied to previously reported autopsy cases of acephate intake. Experimental data suggest that brain MP is involved in acute acephate-induced poisoning, even after a reduction in blood acephate. In autopsy cases with suspected acephate poisoning, the MP level in the brain should be considered in addition to the ChE activity to diagnose the cause of death.


Assuntos
Inibidores da Colinesterase , Inseticidas , Animais , Encéfalo , Camundongos , Compostos Organotiofosforados , Fosforamidas
10.
Environ Sci Pollut Res Int ; 28(40): 57361-57371, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34091843

RESUMO

Since the invasion of the fall armyworm moth (Spodoptera frugiperda) in China in January 2019, damage to maize crops has gradually intensified, and chemical control has become the main control measure. This study aimed to examine methods of effective pest control while monitoring the environmental impact of pesticide use. The effectiveness of S. frugiperda pest control by foliar spraying and root irrigation of maize plants with acephate was determined, and the absorption, distribution, and dissipation of acephate and methamidophos by maize were studied. Field trials showed that acephate treatment at 6000 g a.i. ha-1 was the most effective for controlling S. frugiperda. Acephate and methamidophos were absorbed from the roots, transported upward, and concentrated in the leaves, particularly new leaves. The terminal residues of acephate and methamidophos in maize grains were below detectable levels at 60 days after treatment. The results demonstrate that acephate treatment via root irrigation can more effectively control the infestation of S. frugiperda in maize than acephate treatment via foliar spraying. The translocation and distribution of acephate and methamidophos by root irrigation were more uniform, and the holding efficiency was higher than those in foliar spraying, suggesting an extended period of control efficacy. This pest control method could be utilized to reduce pesticide residues while safely and efficiently controlling S. frugiperda infestation.


Assuntos
Mariposas , Zea mays , Animais , Compostos Organotiofosforados , Fosforamidas , Spodoptera
11.
Chemosphere ; 278: 130476, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33839384

RESUMO

The avoidance behavior is regarded as the method that provides first hand information about the behavior of an organism in the presence of contaminants in the soil. Very little data is found in literature regarding the effect of pesticides on tropical earthworms. Two pesticides, acephate and atrazine which are widely used in Indian tropical area were investigated for their avoidance behavior on standard species, E. fetida (ISO 2007) and on a tropical species, M. posthuma. The avoidance tests are rarely replicated on tropical species, M. posthuma in comparison to standard species, E. fetida or E. andrei. The standard avoidance test (ISO 2007) was taken into consideration for two different species of earthworm. Significant difference in the distribution of earthworms in the control and test soils was found depicting that soil composition plays a vital role in affecting the distribution of worms. The results also show higher sensitivity of E. fetida in comparison to M. posthuma in terms of avoidance response for both the pesticides. For risk assessment, the soil types and indigenous soil species of earthworms must be taken into consideration for evaluation of soil contamination. Avoidance tests forms the basis to study the molecular mechanisms underlying the receptor proteins responsible for the process of chemesthesis in annelids.


Assuntos
Atrazina , Oligoquetos , Praguicidas , Poluentes do Solo , Animais , Atrazina/toxicidade , Aprendizagem da Esquiva , Compostos Organotiofosforados , Praguicidas/toxicidade , Fosforamidas , Solo , Poluentes do Solo/análise , Poluentes do Solo/toxicidade
12.
Artigo em Inglês | MEDLINE | ID: mdl-33558299

RESUMO

The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is global and unprecedented. Although remdesivir has recently been approved by the FDA to treat SARS-CoV-2 infection, no oral antiviral is available for outpatient treatment. AT-527, an orally administered double prodrug of a guanosine nucleotide analog, was previously shown to be highly efficacious and well tolerated in hepatitis C virus (HCV)-infected subjects. Here, we report the potent in vitro activity of AT-511, the free base of AT-527, against several coronaviruses, including SARS-CoV-2. In normal human airway epithelial cells, the concentration of AT-511 required to inhibit replication of SARS-CoV-2 by 90% (EC90) was 0.47 µM, very similar to its EC90 against human coronavirus (HCoV)-229E, HCoV-OC43, and SARS-CoV in Huh-7 cells. Little to no cytotoxicity was observed for AT-511 at concentrations up to 100 µM. Substantial levels of the active triphosphate metabolite AT-9010 were formed in normal human bronchial and nasal epithelial cells incubated with 10 µM AT-511 (698 ± 15 and 236 ± 14 µM, respectively), with a half-life of at least 38 h. Results from steady-state pharmacokinetic and tissue distribution studies of nonhuman primates administered oral doses of AT-527, as well as pharmacokinetic data from subjects given daily oral doses of AT-527, predict that twice daily oral doses of 550 mg AT-527 will produce AT-9010 trough concentrations in human lung that exceed the EC90 observed for the prodrug against SARS-CoV-2 replication. This suggests that AT-527 may be an effective treatment option for COVID-19.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , Guanosina Monofosfato/análogos & derivados , Guanosina/farmacologia , Fosforamidas/farmacologia , Pró-Fármacos/farmacologia , SARS-CoV-2/efeitos dos fármacos , Administração Oral , Animais , COVID-19/virologia , Linhagem Celular , Linhagem Celular Tumoral , Chlorocebus aethiops , Coronavirus Humano 229E/metabolismo , Coronavirus Humano OC43/metabolismo , Cricetinae , Células Epiteliais/virologia , Guanosina Monofosfato/farmacologia , Humanos , Pulmão/virologia , SARS-CoV-2/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
13.
World J Microbiol Biotechnol ; 36(10): 155, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32951077

RESUMO

Acephate is widely used in agriculture, but its poisonous metabolites and poor sorption characteristics make it a serious environmental pollutant and toxicant to human health. To screen novel bacteria for biodegradation of acephate and uncover its degradation pathway, a strain called NDZ that is capable of utilizing acephate as a sole carbon and energy source was isolated from severely contaminated cultivated land. The bacterium was identified as Bacillus paramycoides based on 16S rDNA sequence analyses. The growth and degradation capacities of B. paramycoides NDZ under different conditions were studied using optical density at 600 nm (OD600) and high-performance liquid chromatography (HPLC). The results showed that B. paramycoides NDZ can grow well with acephate as its sole carbon source (OD600 = 0.76), and degraded about 76% of acephate in mineral salt medium with an initial concentration of 500 mg/L within 48 h. The results of response surface methodology revealed the optimal conditions for degradation was 36 ℃ and pH 6.85 with 526 mg/L acephate. Gas chromatography-mass spectrometry showed that methamidophos was the main metabolite of B. paramycoides NDZ, different from the degradation products of high-temperature steam (121 °C, 103 kPa). Based on the detection of this intermediate, we inferred that acephate was degraded to methamidophos through hydrolysis of the amide linkage, after which methamidophos was degraded to some small molecules, which can be metabolized easily by the bacterium. In summary, B. paramycoides NDZ is a potentially useful bacterium for acephate degradation and remediation of contaminated soils.


Assuntos
Bacillus/crescimento & desenvolvimento , Bacillus/isolamento & purificação , Compostos Organotiofosforados/química , Compostos Organotiofosforados/isolamento & purificação , Fosforamidas/química , Bacillus/classificação , Bacillus/genética , Biodegradação Ambiental , DNA Bacteriano/genética , DNA Ribossômico/genética , Cromatografia Gasosa-Espectrometria de Massas , Hidrólise , Metabolômica , RNA Ribossômico 16S/genética , Microbiologia do Solo
14.
J Environ Sci Health B ; 55(11): 951-958, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32698655

RESUMO

In this study, new polymers containing amides (TrisPS-Ntaa, and TrisPS-Ntaa-Fc) were synthesized by condensation reaction for qualitative identification of insecticides. The synthesized polymers, including amides were investigated by infrared spectroscopy (IR), scanning electron microscopy-energy dispersion X- ray spectrometry (SEM-EDX), and gel permeation chromatography (GPC). Then, acetylcholinesterase enzyme (AChE) was covalently immobilized on these polymers to improve properties (including activity, reusability, and storage stability). Accordingly, organophosphate (malathion, acephate, chlorpyrifos methyl) and carbamate (carbofuran, methiocarb, methomyl), which are used to prevent harmful organisms in some agricultural products were enzymatically determined based on their inhibitory activity on AChE.


Assuntos
Carbamatos/análise , Inseticidas/análise , Organofosfatos/análise , Polímeros/química , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Amidas/química , Carbofurano/análise , Clorpirifos/análogos & derivados , Clorpirifos/análise , Inibidores da Colinesterase/análise , Inibidores da Colinesterase/farmacologia , Enzimas Imobilizadas/química , Enzimas Imobilizadas/metabolismo , Inseticidas/farmacologia , Malation/análise , Metomil/análise , Compostos Organotiofosforados/análise , Fosforamidas , Espectrometria por Raios X , Espectrofotometria Infravermelho
15.
Biomolecules ; 10(3)2020 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-32168777

RESUMO

Many bacteria have the potential to use specific pesticides as a source of carbon, phosphorous, nitrogen and sulphur. Acephate degradation by microbes is considered to be a safe and effective method. The overall aim of the present study was to identify acephate biodegrading microorganisms and to investigate the degradation rates of acephate under the stress of humic acid and most common metal ions Fe(III) and copper Cu(II). Pseudomonas azotoformanss strain ACP1, Pseudomonas aeruginosa strain ACP2, and Pseudomonas putida ACP3 were isolated from acephate contaminated soils. Acephate of concentration 100 ppm was incubated with separate strain inoculums and periodic samples were drawn for UV-visible, FTIR (Fourier-transform infrared spectroscopy) and MS (Mass Spectrometry) analysis. Methamidophos, S-methyl O-hydrogen phosphorothioamidate, phosphenothioic S-acid, and phosphenamide were the major metabolites formed during the degradation of acephate. The rate of degradation was applied using pseudo-first-order kinetics to calculate the half-life (t1/2) values, which were 14.33-16.72 d-1 (strain(s) + acephate), 18.81-21.50 d-1 (strain(s) + acephate + Cu(II)), 20.06 -23.15 d-1 (strain(s) + acephate + Fe(II)), and 15.05-17.70 d-1 (strains + acephate + HA). The biodegradation efficiency of the three bacterial strains can be ordered as P. aeruginosa > P. putida > P. azotoformans. The present study illustrated the decomposition mechanism of acephate under different conditions, and the same may be applied to the removal of other xenobiotic compounds.


Assuntos
Cobre/metabolismo , Substâncias Húmicas/microbiologia , Ferro/metabolismo , Compostos Organotiofosforados/metabolismo , Fosforamidas/metabolismo , Pseudomonas/metabolismo , Microbiologia do Solo , Solo , Biodegradação Ambiental
16.
Cancer Lett ; 478: 45-55, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32160976

RESUMO

Multiple myeloma (MM) is an incurable hematological malignancy, for which novel effective therapies are urgently needed. We synthesized a novel phosphoramide compound, DCZ0847, showing a potent anti-myeloma activity both in vitro and in vivo. DCZ0847 showed high cytotoxicity towards primary MM cells but had no effect on normal cells and was well tolerated in vivo. The anti-myeloma activity of DCZ0847 was associated with inhibition of cell proliferation; promotion of cell apoptosis via mitochondrial transmembrane potential collapse and caspase-mediated extrinsic or intrinsic apoptotic pathways; and the induction of G2/M phase arrest via downregulation of CDC25C, CDK1, and cyclin B1. In particular, DCZ0847 induced DNA damage and triggered a DNA-damage response by enhancing the levels of γ-H2A.X, phosphorylated (p)-ATM, p-ATR, p-Chk1, and p-Chk2. Additionally, DCZ0847 was able to overcome the bone marrow stromal cells-induced proliferation of MM cells and blocked JAK2/STAT3 signaling. Importantly, DCZ0847 acted synergistically with bortezomib, with the combination exerting greater cytotoxic effects in vitro and in vivo. Together, our results indicate that DCZ0847, alone or in combination with bortezomib, may represent a potential new therapy for patients with MM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Fosforamidas/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Humanos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mieloma Múltiplo/metabolismo , Fosforamidas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Angew Chem Int Ed Engl ; 59(22): 8451-8455, 2020 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-32101637

RESUMO

A catalytic diastereo- and enantioselective method for the preparation of complex tertiary homoallylic alcohols containing a vicinal quaternary carbon stereogenic center and a versatile alkenylboronic ester is disclosed. Transformations are promoted by 5 mol % of a readily available copper catalyst bearing a bulky monodentate phosphoramidite ligand, which is essential for attaining both high dr and er. Reactions proceed with a wide variety of ketones and allylic 1,1-diboronate reagents, which enables the efficient preparation of diverse array of molecular scaffolds.


Assuntos
Alcenos/química , Compostos de Boro/química , Cobre/química , Cetonas/química , Catálise , Ligantes , Fosforamidas/química , Estereoisomerismo
18.
J Gastroenterol ; 55(6): 640-652, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32065330

RESUMO

BACKGROUND: The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis. METHODS: In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs). RESULTS: Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%) experienced AEs compared with Cohort 1 (68.2%), but the incidence of treatment-related AEs was similar. Most AEs were mild-to-moderate in severity and no patients discontinued due to an AE. There was one serious AE (cataract) in a patient in Cohort 2, which was not considered related to treatment. All patients achieved sustained virologic response 12 weeks after EOT (SVR12). No incidences of viral relapse were observed during follow-up. CONCLUSIONS: In HCV GT1- and GT2-infected Japanese patients, treatment with JNJ-4178 was well tolerated and resulted in 100% of patients achieving SVR12.


Assuntos
Antivirais/administração & dosagem , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Adulto , Idoso , Alanina/administração & dosagem , Alanina/análogos & derivados , Antivirais/efeitos adversos , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Combinação de Medicamentos , Feminino , Seguimentos , Genótipo , Hepacivirus/isolamento & purificação , Hepatite C Crônica/virologia , Humanos , Indóis/administração & dosagem , Japão , Masculino , Pessoa de Meia-Idade , Fosforamidas/administração & dosagem , Simeprevir/administração & dosagem , Resposta Viral Sustentada , Resultado do Tratamento , Uridina/administração & dosagem , Uridina/análogos & derivados
19.
J Hazard Mater ; 389: 122129, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31972525

RESUMO

Novel green nanocomposite from mesoporous MCM-41 and Co3O4 was synthesized from rice husk based silica gel and using the green extract of Peach leaves as reducing reagent. The composite was labeled as RH-MCM-41/Co3O4 and characterized by different techniques as green photocatalyst in the degradation of Acephate pesticide under visible light illumination. The composite showed well developed spherical MCM-41 particles decorated by nano Co3O4 nanoparticles with stunning surface area and low bandgap energy (1.51 eV). The composite displayed superior photocatalytic activities in the oxidation of Acephate which reflected in a complete degradation of different concentrations of it after 40 min (50 mg/L), 60 min (100 mg/L), 100 min (150 mg/L) and 140 min (200 mg/L) using 0.25 g of the composite. The complete removal of the present TOC for treatment of 100 mg/L acephate was achieved using 0.25 g after 70 min reflecting the formation of intermediate compounds during the oxidation steps. The reported intermediate compounds are CH3C(O)NH2, CH3O(CH3S)P(O)NH2, (CH3O)2P(O)SCH3, CH3OP(O)(OH)2, CH3SS(O)2CH3, and (COOH)2. All the formed intermediate compounds were degraded under the visible light photocatalytic activity of RH-MCM-41/Co3O4 into NO3-, SO42-, PO43-, and CO2 as final products.


Assuntos
Cobalto/química , Nanocompostos/química , Compostos Organotiofosforados/química , Óxidos/química , Praguicidas/química , Fosforamidas/química , Sílica Gel/química , Dióxido de Silício/química , Catálise/efeitos da radiação , Reutilização de Equipamento , Concentração de Íons de Hidrogênio , Luz , Nanopartículas Metálicas/química , Oryza/química , Oxirredução , Folhas de Planta/química , Prunus persica/química , Sílica Gel/síntese química , Dióxido de Silício/síntese química
20.
Chemosphere ; 245: 125597, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31864041

RESUMO

Acephate is an organophosphate pesticide. It is widely used. However, whether it inhibits androgen synthesis and metabolism remains unclear. In the current study, we investigated the effect of acephate on the inhibition of androgen synthetic and metabolic pathways in rat immature Leydig cells after 3-h culture. Acephate inhibited basal androgen output in a dose-dependent manner with the inhibition starting at 0.5 µM. It significantly inhibited luteinizing hormone and 8-Br-cAMP stimulated androgen output at 50 µM. It significantly inhibited progesterone-mediated androgen output at 50 µM. Further study demonstrated that acephate down-regulated the expression of Hsd3b1 and its protein at ≥ 0.5 µM, Lhcgr at 5 µM and Star at 50 µM. Acephate directly blocked rat testicular HSD3B1 activity at 50 µM. Acephate did not affect other androgen synthetic and metabolic enzyme activities as well as ROS production, proliferation, and apoptosis of immature Leydig cells. In conclusion, acephate targets LHCGR, STAR, and HSD3B1, thus blocking androgen synthesis in rat immature Leydig cells and HSD3B1 is being the most sensitive target of acephate.


Assuntos
Androgênios/metabolismo , Células Intersticiais do Testículo/efeitos dos fármacos , Compostos Organotiofosforados/farmacologia , Fosforamidas/farmacologia , 8-Bromo Monofosfato de Adenosina Cíclica/análogos & derivados , 8-Bromo Monofosfato de Adenosina Cíclica/antagonistas & inibidores , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Intersticiais do Testículo/metabolismo , Hormônio Luteinizante/antagonistas & inibidores , Hormônio Luteinizante/metabolismo , Masculino , Complexos Multienzimáticos/antagonistas & inibidores , Progesterona/farmacologia , Progesterona Redutase/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Receptores do LH/antagonistas & inibidores , Esteroide Isomerases/antagonistas & inibidores , Testículo/efeitos dos fármacos , Testículo/metabolismo
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