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1.
Environ Res ; 212(Pt D): 113541, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35640708

RESUMO

The use of the herbicide aminotriazole (3-ATA) in agriculture poses rising concerns about global water-borne contamination. Due to its toxicity which is known to cause cancer and thyroid dysfunction, 3-ATA is considered an important analytical target. Environmental protection agencies worldwide have introduced several directives that set concentration limits for chemicals to combat water pollution. Hence, to evaluate the presence of 3-ATA in water and limit their impact on ecosystems and human health, the development of an efficient real-time monitoring device is the key. The as-synthesized copper oxide decorated multiwall carbon nanotubes at 400 °C (CuO-MWCNT@400) showed remarkable efficiency as modifiers. Under optimal conditions, we explored the direct oxidation of 3-ATA at CuO-MWCNT@400 modified carbon paste electrode (MCPE). With its distinguishing synergistic features like high levels of porosity, stability, and surface area, this structure favoured greater detection, selectivity, and sensitivity. The amperometric i-t curve technique was adopted for the first time for 3-ATA quantification. This technique rendered a good detection sensitivity of 1.65 × 10-8 mol L-1 and anti-interference characteristics for several interferent species, including fungicides, fertilizers, herbicides, inorganic ions, and carbohydrates. Finally, the proof-of-concept was yielded by selective and sensitive detection of 3-ATA from two different samples of spiked water. We believe this work will enhance awareness and garner appreciation of the electrochemical sensor's analytical performance in protecting our environment and water resources.


Assuntos
Herbicidas , Nanotubos de Carbono , Amitrol (Herbicida) , Ecossistema , Humanos , Nanotubos de Carbono/química , Água
2.
Toxicol Lett ; 354: 44-55, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34757178

RESUMO

Disruption of the thyroid hormone system during development can impair brain development and cause irreversible damage. Some thyroid hormone system disruptors act by inhibiting the thyroperoxidase (TPO) enzyme, which is key to thyroid hormone synthesis. For the potent TPO-inhibiting drug propylthiouracil (PTU) this has been shown to result in thyroid hormone system disruption and altered brain development in animal studies. However, an outstanding question is which chemicals beside PTU can cause similar effects on brain development and to what degree thyroid hormone insufficiency must be induced to be able to measure adverse effects in rats and their offspring. To start answering these questions, we performed a perinatal exposure study in pregnant rats with two TPO-inhibitors: the drug methimazole (MMI) and the triazole herbicide amitrole. The study involved maternal exposure from gestational day 7 through to postnatal day 22, to MMI (8 and 16 mg/kg body weight/day) or amitrole (25 and 50 mg/kg body weight/day). Both MMI and amitrole reduced serum T4 concentrations in a dose-dependent manner in dams and offspring, with a strong activation of the hypothalamic-pituitary-thyroid axis. This reduction in serum T4 led to decreased thyroid hormone-mediated gene expression in the offspring's brains and caused adverse effects on brain function, seen as hyperactivity and decreased habituation in preweaning pups. These dose-dependent effects induced by MMI and amitrole are largely the same as those observed with PTU. This demonstrates that potent TPO-inhibitors can induce effects on brain development in rats and that these effects are driven by T4 deficiency. This knowledge will aid the identification of TPO-inhibiting thyroid hormone system disruptors in a regulatory context and can serve as a starting point in search of more sensitive markers of developmental thyroid hormone system disruption.


Assuntos
Amitrol (Herbicida)/toxicidade , Antitireóideos/toxicidade , Inibidores Enzimáticos/toxicidade , Metimazol/toxicidade , Atividade Motora/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Glândula Tireoide/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Modelos Animais de Doenças , Feminino , Exposição Materna/efeitos adversos , Síndromes Neurotóxicas/fisiopatologia , Gravidez , Ratos , Transdução de Sinais/efeitos dos fármacos , Testes de Função Tireóidea
3.
Chemosphere ; 291(Pt 1): 132704, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34715101

RESUMO

In an attempt to alleviate the harmful impact of the flammability of epoxy resin on the environment, amitrole, a herbicide, has been converted to a novel flame retardant (PBA) with lamellar morphology through organophosphorus modification. This material has been utilized to fabricate fire safe epoxy thermosets (EP). EP containing 7.5 wt% PBA undergoes quick self-extinguishment upon ignition. This blend displays a high limiting oxygen index (LOI) value of 34%. More importantly, hazardous products (heat, smoke, toxic gases including CO/CO2) released during combustion of EP, are strongly suppressed in the presence of PBA. The mechanical properties of EP-PBA blends are comparable to those of virgin EP. The tensile strength of EP containing PBA is 90% of that of unmodified EP. The flexural strength of PBA blends is somewhat greater than that for EP containing no additive. A tactful strategy for the transformation of amitrole, a potential environmental contaminant to a benign flame retardant for polymers has been developed.


Assuntos
Retardadores de Chama , Herbicidas , Amitrol (Herbicida) , Resinas Epóxi , Retardadores de Chama/toxicidade , Fósforo , Fumaça
4.
Mol Divers ; 26(1): 717-739, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33608844

RESUMO

1,2,4-Triazole-containing scaffolds are unique heterocyclic compounds present in an array of pharmaceuticals and biologically important compounds used in the drug-discovery studies against cancer cells, microbes, and various types of disease in the human body. This review article summarizes the pharmacological significance of the 1,2,4-triazole-containing scaffolds and highlights the latest strategies for the synthesis of these privileged scaffolds using 3-amino-1,2,4-triazole. This review stimulates further research to find new and efficient methodologies for accessing new 1,2,4-triazole-containing scaffolds which would be very useful for the discover of new drug candidates.


Assuntos
Compostos Heterocíclicos , Triazóis , Amitrol (Herbicida) , Humanos
5.
J Colloid Interface Sci ; 607(Pt 2): 1651-1660, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34592552

RESUMO

The rational integration of chemotherapy and hydroxyl radical (·OH)-mediated chemodynamic therapy (CDT) via functional metal-organic frameworks (MOF) carriers has great potential in cancer therapy. In this work, aminotriazole (3-AT) doped polyhedral metal organic frameworks (denoted as MAF) were prepared by template ligand replacement, where CDT was initiated by Cu2+/Cu+ modulated Fenton reaction and enhanced by effectively regulating the catalase activity with 3-AT. However, a rod-like Cu-MOF with 3-AT served as a ligand was obtained by the hydrothermal method without using template. In contrast to Cu-MOF, pH-responsive MAF was chosen as the carrier for targeted drug delivery due to its higher drug load of 17.6% and relatively uniform size, where doxorubicin (DOX) as a model drug was loaded in its cavity and hyaluronic acid (HA) was coated on its surface via electrostatic interactions (denoted as HA-MAF@DOX). In vitro experiments demonstrated that HA-MAF@DOX had high transport efficiency of DOX, effective regulation of catalase (CAT) activity and enhanced cytotoxicity to HepG2 cells. This work is the first use of enzyme inhibitors as ligands to construct functional MOFs via template ligand replacement for effective regulating enzyme activity, mediating intracellular redox homeostasis and enhancing CDT efficacy, which provides a feasible strategy for the construction the functional MOFs in cancer therapy.


Assuntos
Estruturas Metalorgânicas , Amitrol (Herbicida) , Catalase , Peróxido de Hidrogênio , Concentração de Íons de Hidrogênio , Espécies Reativas de Oxigênio
6.
J Mol Recognit ; 34(11): e2929, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34378825

RESUMO

SPR sensor used for amitrole detection was prepared without using any modification. Molecularly imprinted SPR sensor enabled high selectivity for amitrole pesticide. Amino acid-based functional monomer MATrp was integrated as a recognition element. Tailor-made SPR sensor enables real-time monitoring of amitrole pesticide. Synthetic recognition sites provided by MATrp were prepared without labeling.


Assuntos
Amitrol (Herbicida)/análise , Técnicas Biossensoriais/métodos , Impressão Molecular/métodos , Nanopartículas/química , Ressonância de Plasmônio de Superfície/métodos , Limite de Detecção , Propriedades de Superfície
7.
ChemMedChem ; 16(24): 3672-3690, 2021 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-34278727

RESUMO

Herein we report a microscale parallel synthetic approach allowing for rapid access to libraries of N-acylated aminotriazoles and screening of their inhibitory activity against factor XIIa (FXIIa) and thrombin, which are targets for antithrombotic drugs. This approach, in combination with post-screening structure optimization, yielded a potent 7 nM inhibitor of FXIIa and a 25 nM thrombin inhibitor; both compounds showed no inhibition of the other tested serine proteases. Selected N-acylated aminotriazoles exhibited anticoagulant properties in vitro influencing the intrinsic blood coagulation pathway, but not extrinsic coagulation. Mechanistic studies of FXIIa inhibition suggested that synthesized N-acylated aminotriazoles are covalent inhibitors of FXIIa. These synthesized compounds may serve as a promising starting point for the development of novel antithrombotic drugs.


Assuntos
Amitrol (Herbicida)/farmacologia , Anticoagulantes/farmacologia , Fator XIIa/antagonistas & inibidores , Inibidores de Serino Proteinase/farmacologia , Trombina/antagonistas & inibidores , Acilação , Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/química , Anticoagulantes/síntese química , Anticoagulantes/química , Coagulação Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fator XIIa/metabolismo , Humanos , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade , Trombina/metabolismo
8.
Environ Sci Pollut Res Int ; 28(37): 52225-52235, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34002314

RESUMO

In this work, aminotriazole-modified microcrystalline cellulose microsphere (3-ATAR) containing an abundant nitrogen content as promising adsorbent was prepared via a radiation grafting method for the selective recovery ReO4- in the presence of UO22+ in acidic solution. A series of batch and column adsorption experiments including monocomponent and binary systems were designed for evaluating the adsorption and separation performance of Re(VII) onto 3-ATAR. The 3-ATAR exhibited a good adsorption capacity (max 146.4 mg·g-1) of Re(VII) and a rapid adsorption rate, with equilibrium time of 45 min. In binary solution, the high selectivity coefficients (ßRe/M) indicated that 3-ATAR could separate and recover Re(VII) from U(VI) and other metal ions (Cu(II), Cr(III), Ni(II), Zn(II)). In particular, it was found that the adsorption of Re was almost unaffected in U/Re-bearing solutions no matter how much the U(VI) was changed. In the column experiment, when the concentration of U(VI) was 40 times higher than that of Re(VII), 3-ATAR manifested high Re(VII) selectivity over U(VI) from a synthetic uranium ore leachate. This work demonstrated that 3-ATAR could provide an efficient, selectively, sustainable, and industrially feasible way for Re(VII) to be recovered from uranium ore leachate and other prospective sources.Graphical abstract.


Assuntos
Celulose , Amitrol (Herbicida) , Cinética , Microesferas , Estudos Prospectivos
9.
Mater Sci Eng C Mater Biol Appl ; 125: 112113, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33965117

RESUMO

Novel linear cationic poly(amide aminotriazole)s (PATnD) with secondary amine groups in the backbone were obtained by using azide-alkyne 1,3-dipolar cycloaddition reactions: metal- and solvent-free (thermal conditions, PATTnD) or copper(I)-catalyzed (Sharpless conditions, PATCnD). PATnD were investigated in vitro against strains of E. coli, P. aeruginosa, S. aureus, and S. epidermidis. Hemolytic activity was tested using human red blood cells (hRBC), and very low or no hemolytic activity was observed. The cytotoxicity of PATnD polymers against Human Gingival Fibroblasts (HGnF) cells was concentration-dependent, and significant differences between PATT1D and PATC1D were observed. The ability of these polymers to induce resistance against both Gram-positive and Gram-negative bacteria was also assessed. Studied bacterial strains acquired resistance to catalytic polymers (PATCnD) in initial passages meanwhile resistance to thermal polymers (PATTnD) appears in later passages, being the increase of the minimum inhibitory concentration lower than in catalytic polymers. This result, together with the higher biocidal capacity of thermal polymers compared to catalytic ones, seems to suggest an influence of the regiospecificity of the polymers on their antibacterial characteristics. This study also demonstrates that PAT1D polymers, which do not appear to have strong hydrophobic residues, can exert significant antimicrobial activity against Gram-positive bacteria such as S. epidermidis. This pair of polymers, PATC1D and PATT1D, displays the greatest antimicrobial activity while not causing significant hemolysis along with the lowest susceptibility for resistance development of the polymers evaluated.


Assuntos
Antibacterianos , Anti-Infecciosos , Alcinos , Amidas , Amitrol (Herbicida) , Antibacterianos/farmacologia , Azidas , Escherichia coli , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Humanos , Testes de Sensibilidade Microbiana , Polimerização , Staphylococcus aureus , Água
10.
Plant Cell ; 33(6): 2032-2057, 2021 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-33713138

RESUMO

Signaling events triggered by hydrogen peroxide (H2O2) regulate plant growth and defense by orchestrating a genome-wide transcriptional reprogramming. However, the specific mechanisms that govern H2O2-dependent gene expression are still poorly understood. Here, we identify the Arabidopsis Mediator complex subunit MED8 as a regulator of H2O2 responses. The introduction of the med8 mutation in a constitutive oxidative stress genetic background (catalase-deficient, cat2) was associated with enhanced activation of the salicylic acid pathway and accelerated cell death. Interestingly, med8 seedlings were more tolerant to oxidative stress generated by the herbicide methyl viologen (MV) and exhibited transcriptional hyperactivation of defense signaling, in particular salicylic acid- and jasmonic acid-related pathways. The med8-triggered tolerance to MV was manipulated by the introduction of secondary mutations in salicylic acid and jasmonic acid pathways. In addition, analysis of the Mediator interactome revealed interactions with components involved in mRNA processing and microRNA biogenesis, hence expanding the role of Mediator beyond transcription. Notably, MED8 interacted with the transcriptional regulator NEGATIVE ON TATA-LESS, NOT2, to control the expression of H2O2-inducible genes and stress responses. Our work establishes MED8 as a component regulating oxidative stress responses and demonstrates that it acts as a negative regulator of H2O2-driven activation of defense gene expression.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/fisiologia , Herbicidas/farmacologia , Complexo Mediador/metabolismo , Estresse Oxidativo/fisiologia , Amitrol (Herbicida)/farmacologia , Arabidopsis/efeitos dos fármacos , Proteínas de Arabidopsis/genética , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Complexo Mediador/genética , MicroRNAs , Estresse Oxidativo/efeitos dos fármacos , Paraquat/farmacologia , Plantas Geneticamente Modificadas , Domínios Proteicos , Espécies Reativas de Oxigênio/metabolismo , Ácido Salicílico/metabolismo , Fatores Genéricos de Transcrição/genética , Fatores Genéricos de Transcrição/metabolismo
11.
Plant Signal Behav ; 16(5): 1889251, 2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-33632064

RESUMO

Heterotrimeric G-protein α and ß-subunits regulate H2O2-mediated aerenchyma formation. The rice G-protein γ-subunit, dense and erect panicle 1 (DEP1), is known to interact with the α-subunit and regulate nitrogen utilization and yield. However, it is unclear whether DEP1 regulates cell death for aerenchyma formation in rice roots. Using wild-type WYJ8 and its transgenic line WYJ8(DEP1), we confirmed that DEP1 is involved in H2O2-mediated aerenchyma formation. The rates of aerenchyma formation varied in different parts of the roots in both varieties, with the highest rate in the 4-7 cm segments, reaching a plateau in the 7-8 cm segments. Compared with WYJ8, the aerenchyma area and H2O2 content in WYJ8(DEP1) were increased by 55.98% and 53.37%, respectively; however, the responses of aerenchyma formation to exogenous H2O2 were basically the same in the two varieties. Diphenylene iodonium (DPI) treatment had no effect on H2O2 production and elimination processes in WYJ8, but significantly reduced the activity of the key enzyme that catalyzes H2O2 biosynthesis in WYJ8(DEP1). Importantly, exogenous H2O2 treatment did not offset the effect of the decrease in endogenous H2O2 level caused by DPI on aerenchyma formation. These results indicated that DEP1 enhanced H2O2 biosynthesis and promoted the cell death of the root cortex, thus contributing to aerenchyma development in WYJ8(DEP1).


Assuntos
Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Peróxido de Hidrogênio/metabolismo , Oryza/metabolismo , Proteínas de Plantas/metabolismo , Raízes de Plantas/metabolismo , Transdução de Sinais , Amitrol (Herbicida)/farmacologia , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Oniocompostos/farmacologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética
12.
Spectrochim Acta A Mol Biomol Spectrosc ; 250: 119363, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33422878

RESUMO

Graphitic carbon nitride (g-C3N4) has been shown as a promising visible-light photosensitizer for photodynamic therapy (PDT) application. Nevertheless, its therapeutic efficiency is limited by the low efficiency of visible-light utilization. To overcome this issue, 3-amino-1,2,4-triazole-derived graphitic carbon nitride nanosheets (g-C3N5 NSs) are prepared for PDT application. The addition of nitrogen-rich triazole group into the g-C3N4 motif significantly makes the light absorption of g-C3N5 NSs red-shift with the band gap down to 1.95 eV, corresponding to a absorption edge at a wavelength of 636 nm. g-C3N5 NSs generate superoxide anion radicals (O2•-) and singlet oxygen (1O2) under the irradiation of a low-intensity white light emitting diode. Owing to the high efficiency of visible-light utilization, g-C3N5 NSs show about 9.5 fold photocatalytic activity of g-C3N4 NSs. In vitro anticancer studies based on the results of CCK-8 assay, Calcein-AM/PI cell-survival assay and photo-induced intracellular ROS level analysis in living HeLa cells demonstrate the potential of g-C3N5 NSs as a low-toxic and biocompatible high-efficient photosensitizer for PDT.


Assuntos
Fotoquimioterapia , Amitrol (Herbicida) , Grafite , Células HeLa , Humanos , Compostos de Nitrogênio , Triazóis
13.
PLoS One ; 15(6): e0229891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497076

RESUMO

A facile method has been developed for the synthesis of Schiff bases derived from substituted and unsubstituted 3-amino- and 4-amino-1,2,4-triazoles. Condensation of the aminotrizoles with a variety of aromatic aldehydes afforded desired Schiff bases in excellent yields in 3-5 minutes of exposure to ultra-sound. The synthesized compounds were characterized by means of IR, 1HNMR and Mass spectrometry. The synthesized compounds were also screened for their antibacterial potential against Gram-negative (Escherichia coli, Shigella sonnei, Pseudomonas aeruginosa and Salmonella typhi) and two Gram-positive (Staphylococcus aureus and Bacillus subtilis) strains.


Assuntos
Amitrol (Herbicida)/síntese química , Amitrol (Herbicida)/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Ondas Ultrassônicas , Amitrol (Herbicida)/química , Antibacterianos/química , Bactérias/efeitos dos fármacos , Técnicas de Química Sintética , Testes de Sensibilidade Microbiana , Bases de Schiff/química , Triazóis/química
14.
Hypertens Res ; 43(11): 1192-1203, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32461634

RESUMO

Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2) or the increase of endogenous H2O2 centrally produced by catalase inhibition with 3-amino-1,2,4-triazole (ATZ) injected icv reduces the pressor responses to central angiotensin II (ANG II) in normotensive rats. In the present study, we investigated the changes in the arterial pressure and in the pressor responses to ANG II icv in spontaneously hypertensive rats (SHRs) and 2-kidney, 1-clip (2K1C) hypertensive rats treated with H2O2 injected icv or ATZ injected icv or intravenously (iv). Adult male SHRs or Holtzman rats (n = 5-10/group) with stainless steel cannulas implanted in the lateral ventricle were used. In freely moving rats, H2O2 (5 µmol/1 µl) or ATZ (5 nmol/1 µl) icv reduced the pressor responses to ANG II (50 ng/1 µl) icv in SHRs (11 ± 3 and 17 ± 4 mmHg, respectively, vs. 35 ± 6 mmHg) and 2K1C hypertensive rats (3 ± 1 and 16 ± 3 mmHg, respectively, vs. 26 ± 2 mmHg). ATZ (3.6 mmol/kg of body weight) iv alone or combined with H2O2 icv also reduced icv ANG II-induced pressor response in SHRs and 2K1C hypertensive rats. Baseline arterial pressure was also reduced (-10 to -15 mmHg) in 2K1C hypertensive rats treated with H2O2 icv and ATZ iv alone or combined and in SHRs treated with H2O2 icv alone or combined with ATZ iv. The results suggest that exogenous or endogenous H2O2 acting centrally produces anti-hypertensive effects impairing central pressor mechanisms activated by ANG II in SHRs or 2K1C hypertensive rats.


Assuntos
Amitrol (Herbicida)/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Peróxido de Hidrogênio/administração & dosagem , Hipertensão/tratamento farmacológico , Oxidantes/administração & dosagem , Angiotensina II , Animais , Catalase/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Infusões Intraventriculares , Masculino , Ratos Endogâmicos SHR
15.
World J Microbiol Biotechnol ; 36(5): 67, 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32328869

RESUMO

As the use of the new insensitive munitions compound 3-nitro-1,2,4-triazol-5-one (NTO) increases, wastewaters, runoff and groundwater containing NTO will be generated. Little is known about the fate of NTO during biological wastewater treatment. The objective of this study was to explore the ability of wastewater sludges to promote the biotransformation of NTO. Three different sludges, i.e., anaerobic granular sludge, anaerobic digested sludge, and return activated sludge, were used to study the biotransformation of NTO under anaerobic conditions. Three different electron donor amendments were compared- hydrogen, ethanol, and acetate. Mixed microbial communities in each of the three sludge sources were effective in the reductive biotransformation of NTO. 3-amino-1,2,4-triazol-5-one (ATO) was observed as the major product of NTO biotransformation. The highest maximum specific rate of NTO reduction, about 120 mg NTO/g volatile suspended solids/d, was observed in anaerobic granular sludge with hydrogen or ethanol supplied as electron donors. NTO biotransformation to ATO by anaerobic digested sludge was also studied under denitrifying conditions. In this case, reduction of NTO started only after complete denitrification of added nitrate. An important implication of this paper is that sludge from wastewater treatment plants can rapidly and readily reduce NTO to ATO.


Assuntos
Biotransformação , Nitrocompostos/química , Esgotos/química , Triazóis/química , Águas Residuárias , Amitrol (Herbicida)/química , Anaerobiose , Água Subterrânea , Microbiota , Nitratos , Purificação da Água
16.
J Med Chem ; 63(10): 5324-5340, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32329617

RESUMO

Janus kinases (JAKs) are non-receptor tyrosine kinases that are essential components of the JAK-STAT signaling pathway. Associated aberrant signaling is responsible for many forms of cancer and disorders of the immune system. The present focus is on the discovery of molecules that may regulate the activity of JAK2 by selective binding to the JAK2 pseudokinase domain, JH2. Specifically, the Val617Phe mutation in JH2 stimulates the activity of the adjacent kinase domain (JH1) resulting in myeloproliferative disorders. Starting from a non-selective screening hit, we have achieved the goal of discovering molecules that preferentially bind to the ATP binding site in JH2 instead of JH1. We report the design and synthesis of the compounds and binding results for the JH1, JH2, and JH2 V617F domains, as well as five crystal structures for JH2 complexes. Testing with a selective and non-selective JH2 binder on the autophosphorylation of wild-type and V617F JAK2 is also contrasted.


Assuntos
Amitrol (Herbicida)/química , Amitrol (Herbicida)/metabolismo , Ativadores de Enzimas/química , Ativadores de Enzimas/metabolismo , Janus Quinase 2/química , Janus Quinase 2/metabolismo , Animais , Células HEK293 , Humanos , Ligantes , Ligação Proteica/fisiologia , Células Sf9 , Difração de Raios X/métodos
17.
Plant Cell ; 32(5): 1536-1555, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32132132

RESUMO

Little is known about the factors regulating carotenoid biosynthesis in flowers. Here, we characterized the REDUCED CAROTENOID PIGMENTATION2 (RCP2) locus from two monkeyflower (Mimulus) species, the bumblebee-pollinated species Mimulus lewisii and the hummingbird-pollinated species Mimulus verbenaceus We show that loss-of-function mutations of RCP2 cause drastic down-regulation of the entire carotenoid biosynthetic pathway. The causal gene underlying RCP2 encodes a tetratricopeptide repeat protein that is closely related to the Arabidopsis (Arabidopsis thaliana) REDUCED CHLOROPLAST COVERAGE proteins. RCP2 appears to regulate carotenoid biosynthesis independently of RCP1, a previously identified R2R3-MYB master regulator of carotenoid biosynthesis. We show that RCP2 is necessary and sufficient for chromoplast development and carotenoid accumulation in floral tissues. Simultaneous down-regulation of RCP2 and two closely related paralogs, RCP2-L1 and RCP2-L2, yielded plants with pale leaves deficient in chlorophyll and carotenoids and with reduced chloroplast compartment size. Finally, we demonstrate that M. verbenaceus is just as amenable to chemical mutagenesis and in planta transformation as the more extensively studied M. lewisii, making these two species an excellent platform for comparative developmental genetics studies of closely related species with dramatic phenotypic divergence.


Assuntos
Carotenoides/metabolismo , Mimulus/metabolismo , Proteínas de Plantas/química , Proteínas de Plantas/metabolismo , Plastídeos/metabolismo , Repetições de Tetratricopeptídeos , Amitrol (Herbicida)/farmacologia , Clorofila/metabolismo , Cloroplastos/metabolismo , Regulação para Baixo/genética , Epistasia Genética , Flores/genética , Regulação da Expressão Gênica de Plantas , Funções Verossimilhança , Mutação/genética , Fenótipo , Filogenia , Pigmentação/genética , Folhas de Planta/metabolismo , Plastídeos/ultraestrutura , Relação Estrutura-Atividade , Frações Subcelulares/metabolismo , Tabaco/metabolismo
18.
J Am Chem Soc ; 142(11): 5177-5183, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-32100536

RESUMO

The insufficient intracellular H2O2 level in tumor cells is closely associated with the limited efficacy of chemodynamic therapy (CDT). Despite tremendous efforts, engineering CDT agents with a straightforward and secure H2O2 supplying ability remains a great challenge. Inspired by the balance of H2O2 generation and elimination in cancer cells, herein, a nanozyme-based H2O2 homeostasis disruptor is fabricated to elevate the intracellular H2O2 level through facilitating H2O2 production and restraining H2O2 elimination for enhanced CDT. In the formulation, the disruptor with superoxide dismutase-mimicking activity can convert O2•- to H2O2, promoting the production of H2O2. Simultaneously, the suppression of catalase activity and depletion of glutathione by the disruptor weaken the transformation of H2O2 to H2O. Thus, the well-defined system could perturb the H2O2 balance and give rise to the accumulation of H2O2 in cancer cells. The raised H2O2 level would ultimately amplify the Fenton-like reaction-based CDT efficiency. Our work not only paves a way to engineer alternative CDT agents with a H2O2 supplying ability for intensive CDT but also provides new insights into the construction of bioinspired materials.


Assuntos
Antineoplásicos/uso terapêutico , Peróxido de Hidrogênio/metabolismo , Estruturas Metalorgânicas/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Amitrol (Herbicida)/química , Amitrol (Herbicida)/uso terapêutico , Amitrol (Herbicida)/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Catalase/antagonistas & inibidores , Catálise , Linhagem Celular Tumoral , Tratamento Farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/toxicidade , Feminino , Humanos , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/toxicidade , Camundongos , Nanopartículas/química , Nanopartículas/toxicidade , Oxirredução , Polietilenoglicóis/química , Polietilenoglicóis/uso terapêutico , Polietilenoglicóis/toxicidade
19.
Brain Res Bull ; 153: 266-272, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31545999

RESUMO

Intracerebroventricular (icv) injection of hydrogen peroxide (H2O2), a reactive oxygen species, or the blockade of catalase (enzyme that degrades H2O2 into H2O and O2) with icv injection of 3-amino-1,2,4-triazole (ATZ) reduces the pressor effects of angiotensin II also injected icv. In the present study, we investigated the effects of ATZ injected icv or intravenously (iv) on the pressor responses induced by icv injections of the cholinergic agonist carbachol, which similar to angiotensin II induces pressor responses that depend on sympathoexcitation and vasopressin release. In addition, the effects of H2O2 icv on the pressor responses to icv carbachol were also tested to compare with the effects of ATZ. Normotensive non-anesthetized male Holtzman rats (280-300 g, n = 8-9/group) with stainless steel cannulas implanted in the lateral ventricle were used. Previous injection of ATZ (5 nmol/1 µl) or H2O2 (5 µmol/1 µl) icv similarly reduced the pressor responses induced by carbachol (4 nmol/1 µl) injected icv (13 ± 4 and 12 ± 4 mmHg, respectively, vs. vehicle + carbachol: 30 ± 5 mmHg). ATZ (3.6 mmol/kg of body weight) injected iv also reduced icv carbachol-induced pressor responses (21 ± 2 mmHg). ATZ icv or iv and H2O2 icv injected alone produced no effect on baseline arterial pressure. The treatments also produced no significant change of heart rate. The results show that ATZ icv or iv reduced the pressor responses to icv carbachol, suggesting that endogenous H2O2 acting centrally inhibits the pressor mechanisms (sympathoactivation and/or vasopressin release) activated by central cholinergic stimulation.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Catalase/farmacologia , Hipertensão/fisiopatologia , Amitrol (Herbicida)/farmacologia , Angiotensina II , Animais , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Hipertensão/tratamento farmacológico , Injeções Intraventriculares , Masculino , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio , Vasoconstritores/farmacologia , Vasopressinas
20.
Mikrochim Acta ; 186(8): 565, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31338677

RESUMO

A colorimetric and visual assay is described for the herbicide aminotriazole (ATZ). It is based on the etching of gold nanorods (AuNRs) by iodine which is formed on oxidation of iodide via H2O2. Longitudinal etching of the AuNRs occurs quickly and is accompanied by a color change from dark blue to red. In the absence of ATZ and the presence of active catalase (CAT), H2O2 is quickly decomposed into water, and the AuNRs will not be etched. In the presence of ATZ, CAT is partially deactivated, and this affects the amount of available H2O2 and, consequently, of the iodine. Hence, the color is significantly changed. The color changes can be easily detected with bare eyes. The assay has a linear response in the 5 to 70 µM concentration range, with a detection limit of 1.3 µM and high selectivity for ATZ. It was applied to the determination of ATZ in water and food samples. Graphical abstract A multicolor colorimetric method is developed for aminotriazole (ATZ) detection based on catalase (CAT) deactivation-dependent longitudinal etching of gold nanorods (AuNRs). The color signals can be visually identified. Good detection performances and capability for evaluating ATZ level in water and food samples is demonstrated.


Assuntos
Amitrol (Herbicida)/análise , Catalase/metabolismo , Colorimetria/métodos , Nanotubos/química , Cor , Contaminação de Alimentos/análise , Ouro/química , Herbicidas/análise , Peróxido de Hidrogênio/química , Iodo/química , Limite de Detecção , Poluentes Químicos da Água/análise
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