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1.
Sci Total Environ ; 736: 139600, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32474277

RESUMO

Recent studies have reported potential neurotoxicity and epigenetic alteration associated with exposure to several per- and polyfluoroalkyl substances (PFASs). However, such information is limited to a few compounds (e.g., perfluorooctane sulfonate), primarily based on rodent experiments, and the underlying toxicological mechanism(s) for many PFAS in the environment remain poorly understood. In the present study, we investigated 8:8 perfluoroalkyl phosphinic acid (8:8 PFPiA), an under-studied PFAS with high persistency in the environment and biota, using the zebrafish model. We exposed zebrafish embryos (<4 hpf) to various concentrations of 8:8 PFPiA (0, 0.0116, 0.112, 0.343, 1.34, 5.79 µM) for 144 h. Although there was no significant change in survival, hatchability and malformations, zebrafish locomotor speed at 120 h significantly decreased in dark photoperiod. At 144 h, several genes related to thyroid hormones that are essential for neurodevelopment, including corticotropin releasing hormone b (crhb), iodothyronine deiodinase 3a (dio3a), thyroid-stimulating hormone receptor (tshr) and nkx2 homeobox1 (nkx 2.1), were up-regulated by 8:8 PFPiA at 5.79 µM. 8:8 PFPiA also significantly down-regulated a neurodevelopmental gene, elav like neuron-specific RNA binding protein (elavl3), at 1.34 and 5.79 µM; in addition, one oxidative stress gene was slightly but significantly up-regulated. Further, global DNA methylation was significantly decreased at higher treatment levels, identifying effects of 8:8 PFPiA on epigenetic regulation. However, promoter DNA methylation of selected genes (dio3, tshr, nkx2.1) were not statistically altered, though dio3 methylation showed a decreasing trend with 8:8 PFPiA exposure. Our results specifically advance an understanding of molecular toxicology of PFPiA and more broadly present an approach to define diverse responses during animal alternative assessments of PFASs.


Assuntos
Fluorcarbonetos , Peixe-Zebra , Animais , Metilação de DNA , Epigênese Genética , Ácidos Fosfínicos , Glândula Tireoide
2.
Environ Sci Pollut Res Int ; 27(21): 26943-26953, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32385822

RESUMO

Mesoporous silica impregnate with Cyanex 272 (bis/2,4,4-trimethylpentyl/phosphinic acid) extractant was immobilized into an alginate matrix to obtain a composite sorbent easy to use and applicable in fixed-bed column continuous systems. The sorption efficiency of this material was tested for the recovery of Eu(III) ions from aqueous solutions in batch and continuous mode. The competition among rare earths ions (europium, lanthanum, and lutetium) and among rare earths and calcium or sodium ions was investigated. High calcium concentrations strongly reduce the sorption capacity of the alginate matrix that composes the hybrid material and the Cyanex 272 impregnated into silica powder improves the rare earths' sorption performance in this calcium charged media. The experimental breakthrough curves obtained were satisfactory fitted by Thomas model.


Assuntos
Elementos da Série dos Lantanídeos , Ácidos Fosfínicos , Adsorção , Alginatos , Dióxido de Silício
3.
Environ Sci Technol ; 54(8): 4932-4941, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32202099

RESUMO

This study investigated the tissue-specific accumulation and biotransformation of 6:6 and 8:8 perfluoroalkyl phosphinic acids (PFPiA) in common carp (Cyprinus carpio) during 90 d exposure and 30 d depuration in water in the laboratory. Both 6:6 and 8:8 PFPiAs could quickly accumulate in the carp, and 6:6 PFPiA displayed higher bioaccumulation potential than 8:8 PFPiA. The highest concentrations of PFPiAs were observed in the blood, while the lowest were found in the muscle. The equilibrium dialysis experiment indicated that both PFPiAs had higher binding affinities with the proteins in the fish serum than in liver, which was supported by the molecular docking analysis. The results also indicated that 6:6 PFPiA had higher binding affinities with the serum and liver proteins than 8:8 PFPiA. These results suggested that the tissue-specific distribution of PFPiAs was highly dependent on the binding affinities with the specific proteins. Both in vivo and in vitro experiments consistently indicated that PFPiAs experienced biotransformation and produced perfluoroalkyl phosphonic acids (PFPAs), and biotransformation of 8:8 PFPiA was more active than 6:6 PFPiA. It was worth noting that perfluorohexanonate and perfluorooctanoic acids were identified in fish as metabolites after long-term exposure to PFPiAs for the first time.


Assuntos
Carpas , Poluentes Químicos da Água , Animais , Biotransformação , Simulação de Acoplamento Molecular , Ácidos Fosfínicos , Distribuição Tecidual
4.
Invest Ophthalmol Vis Sci ; 61(3): 3, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32150246

RESUMO

Purpose: In the mammalian retina, cannabinoid type 1 receptors (CB1Rs) are well-positioned to alter inhibitory synaptic function from amacrine cells and, thus, might influence visual signal processing in the inner retina. However, it is not known if CB1R modulates amacrine cells feedback inhibition at retinal bipolar cell (BC) terminals. Methods: Using whole-cell voltage-clamp recordings, we examined the pharmacological effect of CB1R activation and inhibition on spontaneous inhibitory postsynaptic currents (sIPSCs) and glutamate-evoked IPSCs (gIPSCs) from identified OFF BCs in light-adapted rat retinal slices. Results: Activation of CB1R with WIN55212-2 selectively increased the frequency of GABAergic, but not glycinergic sIPSC in types 2, 3a, and 3b OFF BCs, and had no effect on inhibitory activity in type 4 OFF BCs. The increase in GABAergic activity was eliminated in axotomized BCs and can be suppressed by blocking CB1R with AM251 or GABAA and GABAρ receptors with SR-95531 and TPMPA, respectively. In all OFF BC types tested, a brief application of glutamate to the outer plexiform layer elicited gIPSCs comprising GABAergic and glycinergic components that were unaffected by CB1R activation. However, blocking CB1R selectively increased GABAergic gIPSCs, supporting a role for endocannabinoid signaling in the regulation of glutamate-evoked GABAergic inhibitory feedback to OFF BCs. Conclusions: CB1R activation shape types 2, 3a, and 3b OFF BC responses by selectively regulate GABAergic feedback inhibition at their axon terminals, thus cannabinoid signaling might play an important role in the fine-tuning of visual signal processing in the mammalian inner retina.


Assuntos
Receptor CB1 de Canabinoide/fisiologia , Células Bipolares da Retina/fisiologia , Células Amácrinas/metabolismo , Células Amácrinas/fisiologia , Animais , Benzoxazinas/farmacologia , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Endocanabinoides/metabolismo , Retroalimentação Fisiológica/efeitos dos fármacos , Retroalimentação Fisiológica/fisiologia , Feminino , Antagonistas de Receptores de GABA-A/farmacologia , Ácido Glutâmico/farmacologia , Potenciais Pós-Sinápticos Inibidores/efeitos dos fármacos , Potenciais Pós-Sinápticos Inibidores/fisiologia , Masculino , Morfolinas/farmacologia , Naftalenos/farmacologia , Técnicas de Patch-Clamp/métodos , Ácidos Fosfínicos/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/efeitos dos fármacos , Retina , Células Bipolares da Retina/efeitos dos fármacos , Transdução de Sinais/fisiologia
5.
Molecules ; 24(18)2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31547345

RESUMO

Three 1,4,7,10-tetraazacyclododecane-based ligands disubstituted in 1,4-positions with phosphonic acid, phosphonate monoethyl-ester, and H-phosphinic acid pendant arms, 1,4-H4do2p, 1,4-H2do2pOEt, and 1,4-H2Bn2do2pH, were synthesized and their coordination to selected metal ions, Mg(II), Ca(II), Mn(II), Zn(II), Cu(II), Eu(III), Gd(III), and Tb(III), was investigated. The solid-state structure of the phosphonate ligand, 1,4-H4do2p, was determined by single-crystal X-ray diffraction. Protonation constants of the ligands and stability constants of their complexes were obtained by potentiometry, and their values are comparable to those of previously studied analogous 1,7-disubstitued cyclen derivatives. The Gd(III) complex of 1,4-H4do2p is ~1 order of magnitude more stable than the Gd(III) complex of the 1,7-analogue, probably due to the disubstituted ethylenediamine-like structural motif in 1,4-H4do2p enabling more efficient wrapping of the metal ion. Stability of Gd(III)-1,4-H2do2pOEt and Gd(III)-H2Bn2do2pH complexes is low and the constants cannot be determined due to precipitation of the metal hydroxide. Protonations of the Cu(II), Zn(II), and Gd(III) complexes probably takes place on the coordinated phosphonate groups. Complexes of Mn(II) and alkali-earth metal ions are significantly less stable and are not formed in acidic solutions. Potential presence of water molecule(s) in the coordination spheres of the Mn(II) and Ln(III) complexes was studied by variable-temperature NMR experiments. The Mn(II) complexes of the ligands are not hydrated. The Gd(III)-1,4-H4do2p complex undergoes hydration equilibrium between mono- and bis-hydrated species. Presence of two-species equilibrium was confirmed by UV-Vis spectroscopy of the Eu(III)-1,4-H4do2p complex and hydration states were also determined by luminescence measurements of the Eu(III)/Tb(III)-1,4-H4do2p complexes.


Assuntos
Complexos de Coordenação/química , Gadolínio/química , Compostos Heterocíclicos/química , Organofosfonatos/química , Meios de Contraste , Complexos de Coordenação/síntese química , Cristalografia por Raios X , Európio/química , Ligantes , Espectroscopia de Ressonância Magnética , Manganês/química , Ácidos Fosfínicos/química , Potenciometria , Espectrofotometria Ultravioleta , Temperatura
6.
Zygote ; 27(5): 321-328, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31412962

RESUMO

Around 60-80% of oocytes maturated in vivo reached competence, while the proportion of maturation in vitro is rarely higher than 40%. In this sense, butafosfan has been used in vivo to improve metabolic condition of postpartum cows, and can represent an alternative to increase reproductive efficiency in cows. The aim of this study was to evaluate the addition of increasing doses of butafosfan during oocyte maturation in vitro on the initial embryo development in cattle. In total, 1400 cumulus-oocyte complexes (COCs) were distributed in four groups and maturated according to supplementation with increasing concentrations of butafosfan (0 mg/ml, 0.05 mg/ml, 0.1 mg/ml and 0.2 mg/ml). Then, 20 oocytes per group were collected to evaluate nuclear maturation and gene expression on cumulus cells and oocytes and the remaining oocytes were inseminated and cultured until day 7, when blastocysts were collected for gene expression analysis. A dose-dependent effect of butafosfan was observed, with decrease of cleavage rate and embryo development with higher doses. No difference between groups was observed in maturation rate and expression of genes related to oocyte quality. Our results suggest that butafosfan is prejudicial for oocytes, compromising cleavage and embryo development.


Assuntos
Blastocisto/fisiologia , Butilaminas/farmacologia , Técnicas de Maturação in Vitro de Oócitos/veterinária , Oócitos/efeitos dos fármacos , Ácidos Fosfínicos/farmacologia , Animais , Butilaminas/administração & dosagem , Bovinos , Relação Dose-Resposta a Droga , Feminino , Fertilização In Vitro , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Técnicas de Maturação in Vitro de Oócitos/métodos , Oócitos/fisiologia , Ácidos Fosfínicos/administração & dosagem
7.
Chem Biodivers ; 16(7): e1900167, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31145516

RESUMO

A dozen of phosphonic and phosphinic acid derivatives containing pyridine moiety were synthesized and its inhibitory activity toward mushroom tyrosinase was investigated. Moreover, molecular docking of these compounds to the active site of the enzyme was performed. All the compounds (1-10) demonstrated the inhibitory effect with the IC50 and inhibition constants ranging millimolar concentrations. The obtained results indicate that the compounds show different types of inhibition (competitive, noncompetitive, mixed), but all of them are reversible inhibitors. The obtained outcomes allowed to make the structure-activity relationship (SAR) analysis. Compound 4 ([(benzylamino)(pyridin-2-yl)methyl]phenylphosphinic acid) revealed the lowest IC50 value of 0.3 mm and inhibitory constant of Ki 0.076 mm, with noncompetitive type and reversible mechanism of inhibition. According to SAR analysis, introducing bulky phenyl moieties to phosphonic and amino groups plays an important role in the inhibitory potency on activity of mushroom tyrosinase and could be useful in design and development of a new class of potent organophosphorus inhibitors of tyrosinase. Combined results of molecular docking and SAR analysis can be helpful in designing novel tyrosinase inhibitors of desired properties. They may have broad application in food industry and cosmetology.


Assuntos
Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Monofenol Mono-Oxigenase/antagonistas & inibidores , Ácidos Fosfínicos/farmacologia , Ácidos Fosforosos/farmacologia , Agaricus/enzimologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Cinética , Estrutura Molecular , Monofenol Mono-Oxigenase/metabolismo , Ácidos Fosfínicos/química , Ácidos Fosfínicos/isolamento & purificação , Ácidos Fosforosos/química , Ácidos Fosforosos/isolamento & purificação , Relação Estrutura-Atividade
8.
Sci Total Environ ; 676: 290-297, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31048160

RESUMO

Perfluoroalkyl phosphinic acids (PFPiAs, including 6:6, 6:8 and 8:8 PFPiAs) are one kind of emerging perfluoroalkyl substances and usually used as leveling and wetting agents in household cleaning products and pesticide formulations. In this study, zebrafish embryos (6 h post-fertilization [hpf]) were exposed to 6:6, 6:8 and 8:8 PFPiAs individually (0.5, 5 and 50 nM) for 168 hpf. 8:8 PFPiA at 5 and 50 nM reduced the body length, while all treatments of 6:8 and 8:8 PFPiA depressed the heartbeat of the zebrafish larvae. 8:8 PFPiA at 50 nM distinctly enhanced the thyroxine (T4) and triiodothyronine (T3) contents. In a negative feedback mechanism, the three PFPiAs remarkably suppressed the genes responsible for THs regulation (corticotropin-releasing hormone, crh; thyroid stimulating hormone, tshß), and 8:8 PFPiA displayed the strongest effect. In addition, 8:8 PFPiA significantly promoted the gene expressions corresponding to THs transport, metabolism and action (transthyretin, ttr; uridine diphosphate glucuronosyltransferase, ugt1ab; deiodinases, dio1 and dio2; thyroid hormone receptors, trα and trß). As a result, 8:8 PFPiA displayed the strongest thyroid endocrine disrupting effect and significantly affected the growth of zebrafish larvae among the three PFPiAs in the present study.


Assuntos
Disruptores Endócrinos/toxicidade , Ácidos Fosfínicos/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Peixe-Zebra
9.
Biointerphases ; 14(2): 021007, 2019 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053032

RESUMO

Gelatin methacryloyl (GelMA) and lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) photoinitiator are commonly used in combination to produce a photosensitive polymer but there are concerns that must be addressed: the presence of unreacted monomer is well known to be cytotoxic, and lithium salts are known to cause acute kidney injury. In this study, acellular 10% GelMA hydrogels cross-linked with different LAP concentrations and cross-linking illumination times were evaluated for their cytotoxicity, photosensitizing potential, and elastic moduli. Alamar Blue and CyQuant Direct Cell viability assays were performed on human primary renal proximal tubule epithelial cells (hRPTECs) exposed to extracts of each formulation. UV exposure during cross-linking was not found to affect extract cytotoxicity in either assay. LAP concentration did not affect extract cytotoxicity as determined by the Alamar Blue assay but reduced hRPTEC viability in the CyQuant Direct cell assay. Photocatalytic activity of formulation extracts toward NADH oxidation was used as a screening method for photosensitizing potential; longer UV exposure durations yielded extracts with less photocatalytic activity. Finally, elastic moduli determined using nanoindentation was found to plateau to approximately 20-25 kPa after exposure to 342 mJ/cm2 at 2.87 mW of UV-A exposure regardless of LAP concentration. LAP at concentrations commonly used in bioprinting (<0.5% w/w) was not found to be cytotoxic although the differences in cytotoxicity evaluation determined from the two viability assays imply cell membrane damage and should be investigated further. Complete cross-linking of all formulations decreased photocatalytic activity while maintaining predictable final elastic moduli.


Assuntos
Células Epiteliais/efeitos dos fármacos , Gelatina/toxicidade , Hidrogéis/toxicidade , Lítio/toxicidade , Ácidos Fosfínicos/toxicidade , Poli-Hidroxietil Metacrilato/toxicidade , Tecidos Suporte , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Elasticidade , Gelatina/química , Humanos , Hidrogéis/síntese química , Teste de Materiais , Poli-Hidroxietil Metacrilato/síntese química
10.
Inorg Chem ; 58(8): 5196-5210, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30942072

RESUMO

Protonation of a distant, noncoordinated group of metal-based magnetic resonance imaging contrast agents potentially changes their relaxivity. The effect of a positive charge of the drug on the human serum albumin (HSA)-drug interaction remains poorly understood as well. Accordingly, a (dibenzylamino)methylphosphinate derivative of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was efficiently synthesized using pyridine as the solvent for a Mannich-type reaction of tBu3DO3A, formaldehyde, and Bn2NCH2PO2H2 ethyl ester. The ligand protonation and metal ion (Gd3+, Cu2+, and Zn2+) stability constants were similar to those of the parent DOTA, whereas the basicity of the side-chain amino group of the complexes (log KA = 5.8) was 1 order of magnitude lower than that of the free ligand (log KA = 6.8). The presence of one bound water molecule in both deprotonated and protonated forms of the gadolinium(III) complex was deduced from the solid-state X-ray diffraction data [gadolinium(III) and dysprosium(III)], from the square antiprism/twisted square antiprism (SA/TSA) isomer ratio along the lanthanide series, from the fluorescence data of the europium(III) complex, and from the 17O NMR measurements of the dysprosium(III) and gadolinium(III) complexes. In the gadolinium(III) complex with the deprotonated amino group, water exchange is extremely fast (τM = 6 ns at 25 °C), most likely thanks to the high abundance of the TSA isomer and to the presence of a proximate protonable group, which assists the water-exchange process. The interaction between lanthanide(III) complexes and HSA is pH-dependent, and the deprotonated form is bound much more efficaciously (∼13% and ∼70% bound complex at pH = 4 and 7, respectively). The relaxivities of the complex and its HSA adduct are also pH-dependent, and the latter is approximately 2-3 times increased at pH = 4-7. The relaxivity for the supramolecular HSA-complex adduct ( r1b) is as high as 52 mM-1 s-1 at neutral pH (at 20 MHz and 25 °C). The findings of this study stand as a proof-of-concept, showing the ability to manipulate an albumin-drug interaction, and thus the blood pool residence time of the drug, by introducing a positive charge in a side-chain amino group.


Assuntos
Benzilaminas/química , Compostos Heterocíclicos com 1 Anel/química , Elementos da Série dos Lantanídeos/química , Ácidos Fosfínicos/química , Albumina Sérica Humana/química , Gadolínio/química , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ligação Proteica , Prótons , Água/química
11.
Bioorg Med Chem Lett ; 29(9): 1031-1042, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30846252

RESUMO

Synthetic pseudopeptides that fit well with the active site architecture allow the most effective binding to enzymes, similar to native substrates in high-energy transition states. Phosphinic acid peptide analogs that comprise the tetrahedral phosphorus moiety introduced to replace an internal amide bond exert such an isosteric or isoelectronic resemblance, combined with providing other advantageous features, for example, metal complexing properties. Accordingly, they are capable of inhibiting metal-dependent enzymes involved in biological functions in eukaryotic and prokaryotic cells. These enzymes are associated with notorious human diseases, such as cancer, e.g., matrix metalloproteinases, or are etiological factors of protozoal and bacterial infections, e.g., metalloaminopeptidases. The affinity and selectivity of these compounds can be conveniently adjusted, either by structural modification of dedicated side chains or by backbone elongation to enhance specific interactions with the corresponding binding pockets. Recent approaches to the synthesis of these compounds are illustrated by examples of the preparation of rationally designed structures of inhibitors of particular enzymes. Activity against appealing enzymatic targets is presented, along with the molecular mechanisms of action and therapeutic implications. Innovative aspects of phosphinic peptide application, e.g., as activity-based probes, and ligands of complexes of radioisotopes for nuclear medicine are also outlined.


Assuntos
Peptídeos/química , Ácidos Fosfínicos/química , Bactérias/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Metaloproteinases da Matriz/química , Metaloproteinases da Matriz/metabolismo , Metais/química , Peptídeo Sintases/antagonistas & inibidores , Peptídeo Sintases/metabolismo , Peptídeos/síntese química , Peptídeos/metabolismo , Antígeno Prostático Específico/química , Antígeno Prostático Específico/metabolismo
12.
Talanta ; 197: 239-248, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30771930

RESUMO

Monitoring superoxide anion radical (O2•-) in live cells and in vivo is of great significance since O2•- is the precursor of other reactive oxygen species and has been closely associated with various physiological and pathological processes. Herein, we developed a novel mitochondria-targeted fluorescent probe PF-MitoSOX Green in which the phosphinate moiety is utilized to recognize O2•- with high sensitivity and selectivity. Confocal imaging results illustrated that PF-MitoSOX Green can not only detect intracellular O2•-, but also can conveniently visualize its production in cells and Caenorhabditis elegans. The present study illustrates that PF-MitoSOX Green provides a novel approach for imaging and detecting O2•- in live cells and in vivo.


Assuntos
Caenorhabditis elegans/química , Corantes Fluorescentes/química , Mitocôndrias/química , Imagem Óptica , Ácidos Fosfínicos/química , Superóxidos/análise , Animais , Linhagem Celular , Corantes Fluorescentes/síntese química , Estrutura Molecular , Ácidos Fosfínicos/síntese química , Ratos
13.
Bioorg Med Chem Lett ; 29(6): 797-801, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30704811

RESUMO

In the present work, the derivatives of calix[4]arene, thiacalix[4]arene, and sulfonylcalix[4]arene bearing four methylene(phenyl)phosphinic acid groups on the upper rim of the macrocycle were synthesized and studied as inhibitors of human protein tyrosine phosphatases. The inhibitory capacities of the three compounds towards PTP1B were higher than those for protein tyrosine phosphatases TC-PTP, MEG1, MEG2, and SHP2. The most potent sulfonylcalix[4]arene phosphinic acid displayed Ki value of 32 nM. The thiacalix[4]arene phosphinic acid was found to be a low micromolar inhibitor of PTP1B with selectivity over the other PTPs. The kinetic experiments showed that the inhibitors compete with the substrate for the active site of the enzyme. Molecular docking was performed to explain possible binding modes of the calixarene-based phosphinic inhibitors of PTP1B.


Assuntos
Calixarenos/química , Inibidores Enzimáticos/química , Ácidos Fosfínicos/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Calixarenos/síntese química , Calixarenos/metabolismo , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Humanos , Cinética , Simulação de Acoplamento Molecular , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/metabolismo , Ligação Proteica , Proteína Tirosina Fosfatase não Receptora Tipo 1/química , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo
14.
J Med Chem ; 62(4): 1917-1931, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30688452

RESUMO

Metallocarboxypeptidases (MCPs) of the M14 family are Zn2+-dependent exoproteases present in almost every tissue or fluid in mammals. These enzymes perform a large variety of physiological functions and are involved in several pathologies, such as pancreatic diseases, inflammation, fibrinolysis, and cancer. Here, we describe the synthesis and functional/structural characterization of a series of reversible tight-binding phosphinic pseudopeptide inhibitors that show high specificity and potency toward these proteases. Characterization of their inhibitory potential against a large variety of MCPs, combined with high-resolution crystal structures of three selected candidates in complex with human carboxypeptidase A (CPA)1, allowed to decipher the structural determinants governing selectivity for type-A of the M14A MCP family. Further, the phosphinic pseudopeptide framework was exploited to generate an optical probe selectively targeting human CPAs. The phosphinic pseudopeptides presented here constitute the first example of chemical probes useful to selectively report on type-A MCPs activity in complex media.


Assuntos
Carboxipeptidases A/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Oligopeptídeos/farmacologia , Ácidos Fosfínicos/farmacologia , Carboxipeptidases A/química , Carboxipeptidases A/metabolismo , Domínio Catalítico , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/farmacologia , Células HEK293 , Células HeLa , Humanos , Indóis/síntese química , Indóis/farmacologia , Cinética , Microscopia Confocal/métodos , Microscopia de Fluorescência/métodos , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/metabolismo , Ligação Proteica
15.
Glia ; 67(2): 246-262, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565755

RESUMO

Astrocytes express a complex repertoire of intracellular Ca2+ transients (events) that represent a major form of signaling within individual cells and in astrocytic syncytium. These events have different spatiotemporal profiles, which are modulated by neuronal activity. Spontaneous Ca2+ events appear more frequently in distal astrocytic processes and independently from each other. However, little is known about the mechanisms underlying such subcellular distribution of the Ca2+ events. Here, we identify the initiation points of the Ca2+ events within the territory of single astrocytes expressing genetically encoded Ca2+ indicator GCaMP2 in culture or in hippocampal slices. We found that most of the Ca2+ events start in an optimal range of thin distal processes. Our mathematical model demonstrated that a high surface-to-volume of the thin processes leads to increased amplitude of baseline Ca2+ fluctuations caused by a stochastic opening of Ca2+ channels in the plasma membrane. Suprathreshold fluctuations trigger Ca2+ -induced Ca2+ release from the Ca2+ stores by activating inositol 1,4,5-trisphosphate (IP3 ) receptors. In agreement with the model prediction, the spontaneous Ca2+ events frequency depended on the extracellular Ca2+ concentration. Astrocytic depolarization by high extracellular K+ increased the frequency of the Ca2+ events through activation of voltage-gated Ca2+ channels in cultured astrocytes. Our results suggest that the morphological profile of the astrocytic processes is responsible for tuning of the Ca2+ events frequency. Therefore, structural plasticity of astrocytic processes can be directly translated into changes in astrocytic Ca2+ signaling. This may be important for both physiological and pathological astrocyte remodeling.


Assuntos
Astrócitos/metabolismo , Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/ultraestrutura , Benzilaminas/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Células Cultivadas , Técnicas de Cocultura , Embrião de Mamíferos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas GABAérgicos/farmacologia , Hipocampo/citologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Ácidos Fosfínicos/farmacologia , Ratos , Ratos Wistar , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Transfecção
16.
Environ Pollut ; 246: 1-10, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30529933

RESUMO

Aluminum dialkyl phosphinates (ADPs) are a class of promising phosphorus-containing flame retardants, but their environmental fate is not well understood. Sorption and transport behaviors of ADPs, and their hydrolysates dialkyl phosphinic acids (DPAs) were studied by batch and column experiments. ADPs are less mobile in soil columns with more than half (>52.6%) of ADPs retained in the soil and residues in the topmost 2-cm layer account for more than 57% of total residues. Dissolution and dispersion of fine grain ADPs were responsible for the transport of ADPs. Sorption DPAs (logKoc) was significantly related to the lipophilicity of DPAs (logD) (p < 0.05). Soil pH and clay content were the dominant factors governing the sorption and transport of DPAs in soils, indicating the importance of electrostatic interactions. The retardation factors (R) of DPAs derived from leaching experiments were pH-dependent with larger R values in the acidic soil (pH = 4.0) where anionic and neutral species of DPAs coexisted. Both physical and chemical non-equilibrium convection-dispersion equations (CDE) yield appropriate modeling for DPAs transport. In most cases, R values estimated from column tests differed from those derived from the batch experiments, which might be attributed to non-equilibrium sorption processes in dynamic conditions.


Assuntos
Alumínio/química , Retardadores de Chama , Ácidos Fosfínicos/química , Poluentes do Solo/química , Solo/química , Adsorção , Monitoramento Ambiental , Modelos Teóricos , Solubilidade
18.
Epilepsy Res ; 149: 17-20, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30419552

RESUMO

Possible proconvulsant action of GABAB receptor antagonist CGP46381 was studied 3 and 13 days after status epilepticus elicited in 12-day-old rats. GABAA-dependent activity was tested by pentylenetetrazol administration and found different in 15-day-old rats after status epiolepticus but not in the older group. The interaction of the two GABAergic systems should be studied in detail.


Assuntos
Antagonistas de Receptores de GABA-B/uso terapêutico , Ácidos Fosfínicos/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Fatores Etários , Animais , Animais Recém-Nascidos , Convulsivantes/uso terapêutico , Modelos Animais de Doenças , Masculino , Pentilenotetrazol/toxicidade , Pilocarpina/toxicidade , Ratos , Ratos Wistar , Estado Epiléptico/induzido quimicamente
19.
Drug Discov Today ; 24(3): 916-929, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30481556

RESUMO

Phosphinic acid derivatives exhibit diverse biological activities and a high degree of structural diversity, rendering them a versatile tool in the development of new medicinal agents. Pronounced recent progress, coupled with previous research findings, highlights the impact of this moiety in medicinal chemistry. Here, we highlight the most important breakthroughs made with phosphinates with a range of pharmacological activities against many diseases, including anti-inflammatory, anti-Alzheimer, antiparasitic, antihepatitis, antiproliferative, anti-influenza, anti-HIV, antimalarial, and antimicrobial agents. We also provide the current status of the corresponding prodrugs, drug-delivery systems, and drug applications of phosphinic acids in the clinical stage.


Assuntos
Ácidos Fosfínicos/uso terapêutico , Pró-Fármacos/uso terapêutico , Animais , Sistemas de Liberação de Medicamentos , Descoberta de Drogas , Humanos
20.
Langmuir ; 34(51): 15871-15877, 2018 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-30516388

RESUMO

Chemical reactions without an obvious optical signal change, such as fluorescence or color, are difficult to monitor. Often, more advanced analytical techniques such as high-performance liquid chromatography and mass spectroscopy are needed. It would be useful to convert such reactions to those with changes in optical signals. In this work, we demonstrate that fluorescently labeled DNA oligonucleotides adsorbed on nanomaterials can probe such reactions, and oxidation of phosphorus-containing species was used as an example. Various metal oxides were tested, and CeO2 nanoparticles were found to be the most efficient for this purpose. Among phosphate, phosphite, and hypophosphite, only phosphate produced a large signal, indicating its strongest adsorption on CeO2 to displace the DNA. This was further used to screen oxidation agents to convert lower oxidation-state compounds to phosphate, and bleach was found to be able to oxidize phosphite. Canonical discriminant analysis was performed to discriminate various phosphorus species using a sensor array containing different metal oxides. On the basis of this, glyphosate was studied for its adsorption and oxidation. Although this method is not specific enough for selective biosensors, it is useful as a tool to produce sensitive optical signals to follow important chemical transformations.


Assuntos
Cério/química , Glicina/análogos & derivados , Nanopartículas/química , Oligodesoxirribonucleotídeos/química , Ácidos de Fósforo/química , Adsorção , Colorimetria/métodos , Fluorescência , Fluorometria/métodos , Glicina/química , Oxirredução , Ácidos Fosfínicos/química , Ácidos Fosfóricos/química , Ácidos Fosforosos/química
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