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1.
Food Chem ; 334: 127345, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712485

RESUMO

The development of a novel molecularly imprinted solid-phase extraction (MISPE) method for simultaneous preconcentration of imazapyr (IMP), imazapic (IMZ) and imazethapyr (IMT) with determination by HPLC-PAD (High performance liquid chromatography - photodiode-array detector) is proposed. The polymer synthesis was performed using imazethapyr as template molecule and 1-vinylimidazole as functional monomer. The method is based on preconcentration of 100.0 mL of sample through 200.0 mg of molecularly imprinted poly(vinylimidazole-TRIM) (MIP-1VN) at pH 4.0, followed by elution with 2.0 mL of MeOH:CH2Cl2:HAc (34:62:4, v/v). The range of analytical curve (0.29-200.0, 0.21-200.0 and 0.15-200.0 µg L-1), limits of detection (0.09, 0.06 and 0.04 µg L-1) and preconcentration factors (92, 96 and 98) determined for the herbicides, IMP, IMZ and IMT, respectively, were greatly superior when compared with those ones obtained with commercial adsorbents. The analytical method was successfully applied to spiked surface water and rice samples with good results of recovery values (86-107%).


Assuntos
Herbicidas/análise , Impressão Molecular/métodos , Oryza/química , Extração em Fase Sólida/métodos , Poluentes Químicos da Água/análise , Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Alimentos/análise , Imidazóis/análise , Imidazóis/síntese química , Imidazóis/química , Limite de Detecção , Niacina/análogos & derivados , Niacina/análise , Ácidos Nicotínicos/análise , Ácidos Nicotínicos/química , Polivinil/síntese química , Polivinil/química , Sementes/química , Extração em Fase Sólida/instrumentação
2.
PLoS One ; 15(9): e0227397, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32925921

RESUMO

The continuous and sole dependence on imidazolinone (IMI) herbicides for weedy rice control has led to the evolution of herbicide resistance in weedy rice populations across various countries growing IMI herbicide-resistant rice (IMI-rice), including Malaysia. A comprehensive study was conducted to elucidate occurrence, level, and mechanisms endowing resistance to IMI herbicides in putative resistant (R) weedy rice populations collected from three local Malaysian IMI-rice fields. Seed bioassay and whole-plant dose-response experiments were conducted using commercial IMI herbicides. Based on the resistance index (RI) quantification in both experiments, the cross-resistance pattern of R and susceptible (S) weedy rice populations and control rice varieties (IMI-rice variety MR220CL2 and non-IMI-rice variety MR219) to imazapic and imazapyr was determined. A molecular investigation was carried out by comparing the acetohydroxyacid synthase (AHAS) gene sequences of the R and S populations and the MR220CL2 and MR219 varieties. The AHAS gene sequences of R weedy rice were identical to those of MR220CL2, exhibiting a Ser-653-Asn substitution, which was absent in MR219 and S plants. In vitro assays were conducted using analytical grade IMI herbicides of imazapic (99.3%) and imazapyr (99.6%) at seven different concentrations. The results demonstrated that the AHAS enzyme extracted from the R populations and MR220CL2 was less sensitive to IMI herbicides than that from S and MR219, further supporting that IMI herbicide resistance was conferred by target-site mutation. In conclusion, IMI resistance in the selected populations of Malaysian weedy rice could be attributed to a Ser-653-Asn mutation that reduced the sensitivity of the target site to IMI herbicides. To our knowledge, this study is the first to show the resistance mechanism in weedy rice from Malaysian rice fields.


Assuntos
Acetolactato Sintase/genética , Resistência a Herbicidas/genética , Oryza/efeitos dos fármacos , Proteínas de Plantas/genética , Plantas Daninhas/efeitos dos fármacos , Acetoína/análise , Acetoína/metabolismo , Acetolactato Sintase/metabolismo , Substituição de Aminoácidos , Asparagina/genética , Bioensaio , Análise Mutacional de DNA , DNA de Plantas/genética , DNA de Plantas/isolamento & purificação , Ensaios Enzimáticos , Herbicidas/farmacologia , Imidazóis/farmacologia , Lactatos/metabolismo , Malásia , Mutação , Niacina/análogos & derivados , Niacina/farmacologia , Ácidos Nicotínicos/farmacologia , Oryza/genética , Proteínas de Plantas/metabolismo , Plantas Daninhas/genética , Sementes/efeitos dos fármacos , Serina/análise , Serina/genética , Serina/metabolismo , Controle de Plantas Daninhas/métodos
3.
Artigo em Inglês | MEDLINE | ID: mdl-32252378

RESUMO

Imazapyr is a herbicide that can be used in irrigation canals to control a range of aquatic weed species, however, its residual nature, combined with its phytotoxicity to crops at low concentrations, means that the water in canals must be carefully managed following imazapyr application. Residues of the herbicide imazapyr (isopropylamine salt) in irrigation water were analysed and modelled after application to irrigation canals in south-eastern Australia. A treatment program to control delta arrowhead (sagittaria; Sagittaria platyphylla (Engelm.) J.G. Sm.) in over 400 km of irrigation canals was enacted by applying imazapyr to dewatered canals during winter. Following imazapyr application, canals were left dewatered for a period (up to eight weeks) and then refilled. After refilling, canals were ponded for a period (up to 28 days) to allow degradation of imazapyr in the water via photolysis. Upon refilling canals, ~650 water samples containing imazapyr were collected across the treatment area and data modelled to measure the extent of water contamination and to guide efforts to reduce the subsequent irrigation hazard to crops. Modelled data demonstrates that imazapyr behaviour in irrigation water following canal refilling was predictable when 1) amount of imazapyr applied, 2) the dewatered period following herbicide application, 3) the water ponding period, and 4) solar exposure during water ponding were taken into account. Minimising the amount applied (g imazapyr per km of canal) and maximising the time between spraying and refilling (dewatered period) reduced the initial concentration in the water following canal refilling. The amount of imazapyr in the canal water following refilling was reduced by half for every 16 days (confidence interval = 10-38 days) that the canal remained dewatered after imazapyr application. Imazapyr dissipation during the ponding period following canal refilling occurred at a rate that depended on solar exposure. Dissipation did not occur when solar exposure was <8.5 MJ m-2. However, when solar exposure was >10 MJ m-2, imazapyr concentration in the water reduced by half for every 4.4 days of ponding period (confidence interval = 2.9-9.5 days). Our two models, combined with local climate data on solar exposure, can be used by canal managers to determine the optimal time to refill canals so that imazapyr dissipation is maximised, and thus risk of damaging irrigated crops is minimised.


Assuntos
Herbicidas , Imidazóis , Niacina/análogos & derivados , Poluentes Químicos da Água , Irrigação Agrícola , Imidazóis/análise , Niacina/análise , Austrália do Sul , Poluentes Químicos da Água/análise
4.
Biochimie ; 168: 297-306, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31770565

RESUMO

The main function of AChE is the hydrolysis of the neurotransmitter acetylcholine (ACh) at the neuromuscular and in cholinergic brain synapses. In some pathologies, loss of cholinergic neurons may be associated with a deficiency of ACh in specific brain areas. Consequently, the study of new safe drugs that inhibit AChE is important, because they can increase ACh levels in the synaptic cleft without adverse effects. Here, we evaluated the effects of JM-20 (a benzodiazepine-dihydropyridine hybrid molecule) on cholinesterase (ChE) activities from distinct sources (AChE from Electrophorus electricus (EeAChE), human erythrocyte membranes (HsAChE (ghost)), total erythrocyte (HsAChE (erythrocyte)) and BChE from plasma (HsBChE) and purified enzyme from the horse (EcBChE)). Kinetic parameters were determined in the presence of 0.05-1.6 mM of substrate concentration. The interactions ChEs with JM-20 were performed using molecular docking simulations. JM-20 inhibited all tested AChE but not BChE. The IC50 values were 123 nM ± 0.2 (EeAChE), 158 nM ± 0.1 (ghost HsAChE), and 172 nM ± 0.2 (erythrocytic HsAChE). JM-20 caused a mixed type of inhibition (it altered Km and Vmax of AChE). The molecular docking indicated the binding poses and the most plausible active isomer of JM-20. Besides giving important data for future drug design, our results help us understand the mode of action of JM-20 as a specific inhibitor of AChE enzymes.


Assuntos
Acetilcolinesterase/metabolismo , Benzodiazepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Niacina/análogos & derivados , Animais , Desenho de Fármacos , Electrophorus , Cavalos , Humanos , Cinética , Niacina/farmacologia
5.
Bull Environ Contam Toxicol ; 104(1): 121-127, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31807794

RESUMO

Analysis of herbicides sorption behavior in soil is critical in predicting their fate and possible harmful side effects in the environment. Application of polar imidazolinone herbicides is growing in tropical agricultural fields. Imidazolinones have high leaching potential and are persistent. In this study, adsorption-desorption of imazapic and imazapyr herbicides were evaluated in different types of Malaysian agricultural soils. Effects of soil parameters were also investigated on the soils' sorption capacities. The adsorption data fitted best to Freundlich isotherm (R2 > 0.991). The herbicides adsorptions were physical and spontaneous processes as ΔG values were negative and below 40 kJ/mol. The adsorption correlated positively with clay content, total organic carbon (TOC) content, and cation exchange capacity (CEC). There were strong negative correlations between hysteresis index and these factors indicating their importance in imidazolinones immobilization and, thus, their pollution reduction in the environment.


Assuntos
Herbicidas/análise , Imidazóis/análise , Niacina/análogos & derivados , Ácidos Nicotínicos/análise , Poluentes do Solo/análise , Adsorção , Agricultura , Argila , Monitoramento Ambiental , Niacina/análise , Solo
6.
Sci Rep ; 9(1): 18248, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796756

RESUMO

Vascular dementia (VaD) is a complex disorder caused by reduced blood flow in the brain. However, there is no effective pharmacological treatment option available until now. Here, we reported that low-dose levamlodipine besylate could reverse the cognitive impairment in VaD mice model of right unilateral common carotid arteries occlusion (rUCCAO). Oral administration of levamlodipine besylate (0.1 mg/kg) could reduce the latency to find the hidden platform in the MWM test as compared to the vehicle group. Furthermore, vehicle-treated mice revealed reduced phospho-CaMKII (Thr286) levels in the hippocampus, which can be partially restored by levamlodipine besylate (0.1 mg/kg and 0.5 mg/kg) treatment. No significant outcome on microglia and astrocytes were observed following levamlodipine besylate treatment. This data reveal novel findings of the therapeutic potential of low-dose levamlodipine besylate that could considerably enhance the cognitive function in VaD mice.


Assuntos
Demência Vascular/tratamento farmacológico , Niacina/análogos & derivados , Nootrópicos/uso terapêutico , Anlodipino , Animais , Astrócitos/efeitos dos fármacos , Vasos Sanguíneos/efeitos dos fármacos , Modelos Animais de Doenças , Camundongos , Microglia/efeitos dos fármacos , Niacina/administração & dosagem , Niacina/uso terapêutico , Nootrópicos/administração & dosagem
7.
Mutat Res ; 845: 403077, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31561891

RESUMO

1,4-Dihydropyridines (1,4-DHP) possess important biochemical and pharmacological properties, including antioxidant and antimutagenic activities. AV-153-Na, an antimutagenic and DNA-repair enhancing compound was shown to interact with DNA by intercalation. Here we studied DNA binding of several AV-153 salts to evaluate the impact of AV-153 modifications on its DNA binding capacity, the ability to scavenge the peroxynitrite, to protect HeLa and B-cells cells against DNA damage. Affinity of the AV-153 salts to DNA measured by a fluorescence assay was dependent on the metal ion forming a salt in position 4 of the 1,4-DHP, and it decreased as follows: Mg > Na > Ca > Li > Rb > K. AV-153-K and AV-153-Rb could not react chemically with peroxynitrite as opposed to AV-153-Mg and AV-153-Ca, the latter increased the decomposition rate of peroxynitrite. AV-153-Na and AV-153-Ca effectively reduced DNA damage induced by peroxynitrite in HeLa cells, while AV-153-K and AV-153-Rb were less effective, AV-153-Li did not protect the DNA, and AV-153-Mg even caused DNA damage itself. The Na, K, Ca and Mg AV-153 salts were also shown to reduce the level of DNA damage in human B-cells from healthy donors. Thus, metal ions modify both DNA-binding and DNA-protecting effects of the AV-153 salts.


Assuntos
Antioxidantes/farmacologia , Dano ao DNA/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Substâncias Intercalantes/farmacologia , Metais/farmacologia , Niacina/análogos & derivados , Antioxidantes/toxicidade , Linfócitos B/efeitos dos fármacos , Ensaio Cometa , Quebras de DNA de Cadeia Simples , Reparo do DNA , Di-Hidropiridinas/toxicidade , Interações Medicamentosas , Células HeLa , Humanos , Substâncias Intercalantes/toxicidade , Niacina/farmacologia , Niacina/toxicidade , Estresse Oxidativo , Ácido Peroxinitroso/toxicidade , Proteínas Recombinantes/farmacologia , Análise de Célula Única , Produtos do Gene tat do Vírus da Imunodeficiência Humana/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacologia
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 223: 117306, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31255862

RESUMO

In recent years, levamlodipine (LAML) has been widely used as a common drug for the treatment of hypertension. However, no reports exist that focus on the binding process of LAML with the transport proteins present in blood circulation. Here, several spectroscopy techniques, molecular docking and a molecular dynamics simulation were employed to comprehensively analyze the mechanism underlying the interaction between bovine hemoglobin (BHb) and LAML, as well as the effect of other drugs on the BHb-LAML system. The results indicated that a stable BHb-LAML complex was formed and that the binding site for LAML was located at ß-37 tryptophan in the central cavity of BHb. Van der Waals force and hydrogen bonds played major roles in this binding process, and the number of binding sites (n) in the binary system was approximately equal to 1. Multiple spectroscopy experiments (FT-IR and three-dimensional fluorescence spectrometry) and a dynamics simulation revealed that LAML could induce a conformational in BHb and that the microenvironment of Trp/Tyr changed. Interestingly, the values of the binding constant between LAML and BHb significantly increased due to the effect of rofecoxib, propranolol and enalapril. Meanwhile, these drugs did not produce synergistic or negative synergistic effects on the LAML binding with BHb. These results provide new insight into the transport mechanisms for LAML in the human body.


Assuntos
Hemoglobinas/metabolismo , Simulação de Acoplamento Molecular , Niacina/análogos & derivados , Análise Espectral , Animais , Bovinos , Fluorescência , Hemoglobinas/química , Cinética , Niacina/química , Niacina/metabolismo , Ligação Proteica , Conformação Proteica , Espectrometria de Fluorescência , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Termodinâmica
9.
J Med Chem ; 62(6): 3088-3106, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30843696

RESUMO

P2Y12 antagonists are widely used as antiplatelet agents for the prevention and treatment of arterial thrombosis. Based on the scaffold of a known P2Y12 antagonist AZD1283, a series of novel bicyclic pyridine derivatives were designed and synthesized. The cyclization of the ester substituent on the pyridine ring to the ortho-methyl group led to lactone analogues of AZD1283 that showed significantly enhanced metabolic stability in subsequent structure-pharmacokinetic relationship studies. The metabolic stability was further enhanced by adding a 4-methyl substituent to the piperidinyl moiety. Compound 58l displayed potent inhibition of platelet aggregation in vitro as well as antithrombotic efficacy in a rat ferric chloride model. Moreover, 58l showed a safety profile that was superior to what was observed for clopidogrel in a rat tail-bleeding model. These results support the further evaluation of compound 58l as a promising drug candidate.


Assuntos
Descoberta de Drogas , Niacina/análogos & derivados , Inibidores da Agregação de Plaquetas/farmacologia , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Receptores Purinérgicos P2Y12/efeitos dos fármacos , Sulfonamidas/farmacologia , Animais , Humanos , Masculino , Niacina/química , Niacina/farmacocinética , Niacina/farmacologia , Inibidores da Agregação de Plaquetas/química , Inibidores da Agregação de Plaquetas/farmacocinética , Antagonistas do Receptor Purinérgico P2Y/química , Antagonistas do Receptor Purinérgico P2Y/farmacocinética , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética
10.
Neurol Res ; 41(5): 385-398, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30821663

RESUMO

OBJECTIVE: JM-20, a novel hybrid synthetic molecule, has been reported to have antioxidant, mitoprotective, anti-excitotoxic, anti-apoptotic and anti-inflammatory properties. However, the neuroprotective effect of JM-20 against memory impairment in preclinical AD-like models has not been analyzed. The aim of this study was to evaluate the potential neuroprotection of JM-20 that preserves essential memory process from cholinergic dysfunction and other molecular damages. METHODS: The effects of JM-20 on scopolamine (1 mg/kg)-induced cognitive disorders were studied. Male Wistar rats (220-230 g) were treated with JM-20 and/or scopolamine, and behavioral tasks were performed. The AChE activity, superoxide dismutase activity, catalase activity, MDA and T-SH level on brain tissue were determined by spectrophotometric methods. Mitochondrial functionality parameters were measured after behavioral tests. Histological analyses on hippocampus and prefrontal cortex were processed with hematoxylin and eosin, and neuronal and axonal damage were determined. RESULTS: The behavioral, biochemical and histopathological studies revealed that oral pre-treatment with JM-20 (8 mg/kg) significantly attenuated the scopolamine-induced memory deficits, mitochondrial malfunction, oxidative stress, and prevented AChE hyperactivity probably due to specific inhibition of AChE enzyme. It was also observed marked histological protection on hippocampal and prefrontal-cortex regions. CONCLUSIONS: The multimodal action of this molecule could mediate the memory protection here observed and suggest that it may modulate different pathological aspects of memory deficits associated with AD in humans.


Assuntos
Benzodiazepinas/farmacologia , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Memória/efeitos dos fármacos , Niacina/análogos & derivados , Nootrópicos/farmacologia , Acetilcolinesterase/metabolismo , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Niacina/farmacologia , Distribuição Aleatória , Ratos Wistar , Escopolamina
12.
Pak J Pharm Sci ; 32(5(Special)): 2433-2436, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31894030

RESUMO

This study was designed to compare the efficacy of two different racemic antihypertensive drugs on elderly patients with hypertension and their effects on vascular endothelial function and atherosclerosis. A total of 84 elderly hypertensive patients were randomly divided into control and treatment group with 42 patients in each group. The control group was treated with 2.5mg levamlodipine while the treatment group was given 5mg amlodipine. Total effective rate of the treatment group was 90.5%, higher than the control group, that was 71.4% (P<0.05). The time for recovery of related indicators like blood pressure, the total duration of medication were significantly (P<0.05) shorter in the treatment group. Only 1 case of adverse drug reaction was found in the treatment group while 6 cases in control group. Compared to the control group, the treatment group had massive improvement in fingertip pulse volume, flow-mediated dilation of the brachial arteries and endothelin-1 level, carotid intima-media thickness, plaque length & thickness, and blood pressure after the administration. The rate of satisfaction with the in treatment group was 95.3%, higher than that the control group, which was 78.6%. The study concluded that in elderly patients with hypertension, the treatment with 5mg amlodipine enhanced curative effect, fully improved endothelial function & arteriosclerosis and reduced adverse reactions thereby shortening treatment time.


Assuntos
Anlodipino/uso terapêutico , Aterosclerose/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Niacina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Niacina/uso terapêutico , Vasodilatadores/uso terapêutico
13.
J Am Soc Mass Spectrom ; 30(1): 161-173, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30019163

RESUMO

In this article, an analytical methodology to investigate the proteinaceous content in atmospheric size-resolved aerosols collected at the Zeppelin observatory (79 °N, 12 °E) at Ny Ålesund, Svalbard, from September to December 2015, is proposed. Quantitative determination was performed after acidic hydrolysis using ultrahigh-performance liquid chromatography in reversed-phase mode coupled to electrospray ionization tandem mass spectrometry. Chromatographic separation, as well as specificity in the identification, was achieved by derivatization of the amino acids with N-butyl nicotinic acid N-hydroxysuccinimide ester prior to the analysis. The chromatographic run was performed within 11 min and instrumental levels of detection (LODs) were between 0.2 and 8.1 pg injected on the column, except for arginine which exhibited an LOD of 37 pg. Corresponding method LODs were between 0.01 and 1.9 fmol/m3, based on the average air sampling volume of 57 m3. The sum of free amino acids and hydrolyzed polyamino acids was shown to vary within 6-2914 and 0.02-1417 pmol/m3 for particles in sizes < 2 and 2-10 µm in equivalent aerodynamic diameter, respectively. Leucine, alanine, and valine were the most abundant among the amino acids in both aerosol size fractions. In an attempt to elucidate source areas of the collected aerosols, 5- to 10-day 3D backward trajectories reaching the sampling station were calculated. Overall, the method described here provides a first time estimate of the proteinaceous content, that is, the sum of free and polyamino acids, in size-resolved aerosols collected in the Arctic. Graphical Abstract ᅟ.


Assuntos
Aerossóis/análise , Aminoácidos/análise , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Ar/análise , Aminoácidos/química , Regiões Árticas , Atmosfera , Hidrólise , Limite de Detecção , Niacina/análogos & derivados , Niacina/farmacologia , Noruega , Tamanho da Partícula , Proteínas/química , Succinimidas/farmacologia
14.
Pest Manag Sci ; 75(4): 935-941, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30187639

RESUMO

BACKGROUND: Acetohydroxyacid synthase large subunit 1 (Ahasl1) is a multiallelic locus involved in herbicide resistance in sunflower. Ahasl1-1 and Ahasl1-4 alleles harbor different point mutations that lead to different amino acid substitutions (Ala205Val and Trp574Leu, respectively). The objectives of this work were to evaluate the effect of these alleles at the enzymatic and whole-plant levels, and to determine the dominance relationships for imazapyr and metsulfuron-methyl herbicides. RESULTS: Resistant near-isogenic lines showed significantly lower specific AHAS activity than susceptible near-isoline. However, kinetic studies indicated that mutations did not change AHAS pyruvate affinity. Dose-response for six near-isolines carrying different combinations of Ahasl1-1 and Ahasl1-4 alleles and two herbicides (imazapyr and metsulfuron-methyl) were evaluated at whole-plant and enzymatic levels. Ahasl1-1 allele conferred moderate resistance to imazapyr and low resistance to metsulfuron-methyl. Conversely, Ahasl1-4 allele endowed high levels of resistance for both herbicides. Dominance of resistance at whole-plant level showed a semi-dominant behavior among the alleles for both herbicides. CONCLUSION: Ahasl1-4 allele confers higher resistance levels than Ahasl1-1 when evaluated with imazapyr and metsulfuron-methyl. Dominance estimations suggested that both parental lines should carry a resistance trait when developing hybrids. © 2018 Society of Chemical Industry.


Assuntos
Acetolactato Sintase/genética , Sulfonatos de Arila/farmacologia , Helianthus/genética , Resistência a Herbicidas/genética , Herbicidas/farmacologia , Imidazóis/farmacologia , Niacina/análogos & derivados , Proteínas de Plantas/genética , Acetolactato Sintase/metabolismo , Alelos , Helianthus/efeitos dos fármacos , Helianthus/enzimologia , Niacina/farmacologia , Proteínas de Plantas/metabolismo
15.
Neurosci Lett ; 690: 29-35, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30304707

RESUMO

Oxidative stress and mitochondrial dysfunction are two pathophysiological factors often associated with the neurodegenerative process involved in Parkinson's disease (PD). The aim of this study was to investigate the effects of a novel hybrid molecule, named JM-20, in different in vitro and in vivo models of PD induced by rotenone. To perform in vitro studies, SHSY-5Y cells were exposed to rotenone and/or treated with JM-20. To perform in vivo studies male Wistar rats were intoxicated with rotenone (2.5 mg/kg) via intraperitoneal injection and/or treated with JM-20 (40 mg/kg) administered via oral (for 25 days, both treatment). Rats were evaluated for global motor activity by measurement of locomotor activity. In addition, the effects on mortality, general behavior and redox parameters were also investigated. JM-20 protected SHSY-5Y cells against rotenone-induced cytotoxicity, evidenced by a significant diminution of cell death. In in vivo studies, JM-20 prevented rotenone-induced vertical exploration and locomotion frequency reductions, moreover prevented body weight loss and mortality induced by rotenone. It also improved the redox state of rotenone-exposured animals by increasing superoxide dismutase and catalase activities, total tissue-SH levels and decreasing malondialdehyde concentrations. Finally, JM-20 inhibited spontaneous mitochondrial swelling and membrane potential dissipation in isolated rats brain mitochondria. These results demonstrate that JM-20 is a potential neuroprotective agent against rotenone-induced damage in both in vitro and in vivo models, resulting in reduced neuronal oxidative injury and protection of mitochondria from impairment.


Assuntos
Benzodiazepinas/farmacologia , Fármacos Neuroprotetores/farmacologia , Síndromes Neurotóxicas/prevenção & controle , Niacina/análogos & derivados , Rotenona/toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Mitocôndrias/metabolismo , Atividade Motora/efeitos dos fármacos , Niacina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Superóxido Dismutase/metabolismo
16.
J Hazard Mater ; 366: 636-642, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30579230

RESUMO

Imidazolinones as a persistent and active herbicides group have potential risks to non-target organisms in the environment. Biochar is a carbon-rich sorbent used as an amendment to change soil properties and its microbial communities effective on pesticides degradation rate. The present study was the first to compare empty fruit bunch (EFB) of oil palm and rice husk (RH) biomasses as biochar feedstock for remediation of imidazolinones-contaminated soils. Degradations of imazapic, imazapyr, and a mixture of them (Onduty®) was investigated in the presence of the optimized biochars in the soil during a 70-days incubation. Based on the results, the polar herbicides were resistant to hydrolysis degradation. Photolysis rates of the herbicides reduced significantly in the presence of the biochars in the soil. EFB biochar had greater effects due to its chemical compositions and surface functional groups. Photo-degradation of imazapyr was more affected by biochars amendment. The imidazolinones bio-degradation, however, accelerated significantly with the presence of EFB and RH biochars in soil with the greater effects of RH biochar. It was concluded that the application of the optimized EFB and RH biochars as an innovative sustainable strategy has the potential to decrease the persistence of the imidazolinones and minimize their environmental hazards.


Assuntos
Carvão Vegetal/química , Herbicidas/química , Imidazóis/química , Niacina/análogos & derivados , Ácidos Nicotínicos/química , Oryza/química , Óleo de Palmeira/química , Poluentes do Solo/química , Niacina/química , Fotólise
17.
Mol Neurobiol ; 56(1): 502-512, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29725905

RESUMO

Stroke is frequently associated with severe neurological decline and mortality, and its incidence is expected to increase due to aging population. The only available pharmacological treatment for cerebral ischemia is thrombolysis, with narrow therapeutic windows. Efforts aimed to identify new therapeutics are crucial. In this study, we look into plausible molecular and cellular targets for JM-20, a new hybrid molecule, against ischemic stroke in vivo. Male Wistar rats were subjected to 90 min middle cerebral artery occlusion (MCAO) following 23 h of reperfusion. Animals treated with 8 mg/kg JM-20 (p.o., 1 h after reperfusion) showed minimal neurological impairment and lower GABA and IL-1ß levels in CSF when compared to damaged rats that received vehicle. Immunocontent of pro-survival, phosphorylated Akt protein decreased in the cortex after 24 h as result of the ischemic insult, accompanied by decreased number of NeuN+ cells in the peri-infarct cortex, cornu ammonis 1 (CA1) and dentate gyrus (DG) areas. Widespread reactive astrogliosis in both cortex and hippocampus (CA1, CA3, and DG areas) was observed 24 h post-ischemia. JM-20 prevented the activated Akt reduction, neuronal death, and astrocytes reactivity throughout the brain. Overall, the results reinforce the pharmacological potential of JM-20 as neuroprotective agent and provide important evidences about its molecular and cellular targets in this model of cerebral ischemia.


Assuntos
Astrócitos/patologia , Benzodiazepinas/uso terapêutico , Infarto Encefálico/tratamento farmacológico , Encéfalo/patologia , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Neurônios/patologia , Niacina/análogos & derivados , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Benzodiazepinas/farmacologia , Infarto Encefálico/líquido cefalorraquidiano , Infarto Encefálico/patologia , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Morte Celular/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/metabolismo , Gliose/patologia , Infarto da Artéria Cerebral Média/líquido cefalorraquidiano , Interleucina-10/líquido cefalorraquidiano , Interleucina-1beta/líquido cefalorraquidiano , Masculino , Neurônios/efeitos dos fármacos , Niacina/farmacologia , Niacina/uso terapêutico , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Resultado do Tratamento , Ácido gama-Aminobutírico/líquido cefalorraquidiano
18.
Plant Cell Rep ; 37(8): 1201-1213, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29868986

RESUMO

KEY MESSAGE: Mutagenesis had no effect on number of stalks/plot, stalk height, fibre and sucrose content of mutants. Imazapyr tolerance is likely due to a S622N mutation in the acetolactate synthase gene. The herbicidal compound imazapyr is effective against weeds such as Cynodon and Rottboellia species that constrain sugarcane production. This study aimed to compare agronomic characteristics of three imazapyr tolerant mutants (Mut 1, Mut 6 and Mut 7) with the non-mutated N12 control after 18 months of growth, and to sequence the acetolactate synthase (ALS) gene to identify any point mutations conferring imazapyr tolerance. There were no significant differences in the number of stalks/plot, stalk height, fibre and sucrose contents of the mutants compared with the N12 control. However, Mut 1 genotype was more susceptible to the Lepidopteran stalk borer, Eldana saccharina when compared with the non-mutated N12 (11.14 ± 1.37 and 3.89 ± 0.52% internodes bored, respectively), making Mut 1 less desirable for commercial cultivation. Molecular characterisation of the ALS gene revealed non-synonymous mutations in Mut 6. An A to G change at nucleotide position 1857 resulted in a N513D mutation, while a G to A change at nucleotide position 2184 imposed a S622N mutation. Molecular dynamics simulations revealed that the S622N mutation renders an asparagine side chain clash with imazapyr, hence this mutation is effective in conferring imazapyr tolerance.


Assuntos
Acetolactato Sintase/metabolismo , Imidazóis/farmacologia , Niacina/análogos & derivados , Saccharum/efeitos dos fármacos , Saccharum/genética , Acetolactato Sintase/genética , Genótipo , Simulação de Dinâmica Molecular , Mutação/genética , Niacina/farmacologia
19.
Pharmacol Rep ; 70(4): 699-704, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29933207

RESUMO

Ischemic stroke is a major cause of death and disability worldwide. Thrombolysis by tissue plasminogen activator is the only pharmacological treatment approved for clinical practice, but has a narrow therapeutic window and poor efficacy when the cell death cascade is activated. Numerous drugs that are thought to protect neurons against injury have previously failed in human trials despite showing efficacy in experimental models of stroke. Herein, we reviewed the main pre-clinical results of the neuroprotective effects of JM-20, a new hybrid molecule, against brain ischemia. JM-20 appears to protect the brain from ischemic damage by interfering with several elements of the ischemic cascade: antiexcitotoxic, anticalcic, antioxidant, antiapoptotic, and anti-inflammatory. Its ability to protect not only neurons but also glial cells together with its ability to target and preserve mitochondrial function makes JM-20 a promising molecule that may be able to shield the whole neurovascular unit. The multimodal and multi-cell action of JM-20 may explain the high degree of protection observed in a rat model of brain ischemia, as assayed through histological (hematoxylin-eosin, and luxol fast blue staining), neurochemical (glutamate and aspartate levels in cerebrospinal fluid), mitochondrial functionality and behavioural (neurological scale) analysis at doses of 4 and 8mg/kg. Furthermore, the wide therapeutic window of JM-20 of 8h also suggests that this molecule could be of potential interest in situations where brain perfusion is compromised.


Assuntos
Benzodiazepinas/farmacologia , Isquemia Encefálica/prevenção & controle , Niacina/análogos & derivados , Animais , Avaliação Pré-Clínica de Medicamentos , Fármacos Neuroprotetores/farmacologia , Niacina/farmacologia
20.
Med Chem ; 14(8): 851-862, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29669502

RESUMO

BACKGROUND: The Hantzsch ester, diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5- dicarboxylate, has been used as a hydride donor and its various biological effects have been reported. To identify chemotherapeutic agents with apoptotic effects, 21 diethyl 2,6-dimethyl-1,4- dihydropyridine-3,5-dicarboxylates were designed and synthesized; they have not been reported as apoptosis inducers thus far. Their structure-cytotoxicity relationships were investigated. Further biological experiments were performed on the title compound. METHODS: The cytotoxicities of the current synthetic compounds were measured using a clonogenic assay in HCT116 human colon cancer cells. An annexin V staining assay was used to confirm if the title compound induced apoptosis. To identify the synthetic compounds, Nuclear Magnetic Resonance (NMR) spectroscopy and high-resolution mass spectrometry (HR-MS) were conducted. As molecular symmetry was observed in the NMR spectroscopic data, the three dimensional structures were determined from ab initio calculations and X-ray crystallography. RESULTS: The results obtained from NMR spectroscopy, ab initio calculations, and X-ray crystallography revealed that the diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate derivatives synthesized in this research have symmetric structures. The cytotoxicities of the 21 derivatives were tested in the HCT116 human colon cancer cell lines, and their half-maximal cell growth inhibitory concentrations ranged between 16.29 and 68.88 µM. Structure-cytotoxicity relationships demonstrated that bulky substitutions were preferred, para-positioned substituents tended to have better cytotoxic values, and the polarity may have a function as well. The cytotoxicity of the title compound in HCT116 colon cancer cells was mediated through apoptotic cell death. CONCLUSION: To obtain chemotherapeutic agents that induce apoptosis, 21 diethyl 2,6-dimethyl- 1,4-dihydropyridine-3,5-dicarboxylates were designed and synthesized. NMR spectroscopy, ab initio calculations, and X-ray crystallography demonstrated that the diethyl 2,6-dimethyl-1,4- dihydropyridine-3,5-dicarboxylate derivatives synthesized in this research had symmetric structures. Even if the half-maximal cell growth inhibitory concentrations of the 21 derivatives did not show dramatic inhibitory activity against HCT116 human colon cancer cells, small changes in the structure affected the anticancer activities. Treatment with diethyl 4-(4-chlorophenyl)-2,6- dimethyl-1,4-dihydropyridine-3,5-dicarboxylate substantially reduced the cell viability and the cytotoxicity against HCT116 colon cancer cells was mediated through apoptotic cell death. As the ability of diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates to induce apoptosis has not been previously reported, we have now reported their design, synthesis, cytotoxicity, and structureactivity relationships.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Di-Hidropiridinas/farmacologia , Ésteres/farmacologia , Niacina/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Caspase 7/metabolismo , Caspase 9/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Di-Hidropiridinas/síntese química , Di-Hidropiridinas/química , Ésteres/síntese química , Ésteres/química , Células HCT116 , Humanos , Modelos Químicos , Niacina/análogos & derivados , Niacina/síntese química , Teoria Quântica , Relação Estrutura-Atividade
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