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1.
J Hazard Mater ; 422: 126872, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34399212

RESUMO

Herein, a dual-function Zeolitic Imidazole Frameworks (ZIFs) ZIF-90 grafted with malononitrile by Knoevenagel reaction and following with an amidoximation reaction to form an efficient U (VI) adsorbent (ZIF-90-AO). The strong chelation power of amidoxime groups (AO) with uranium and ZIF-90's mesoporous structure afforded ZIF-90-AO high maximum uranium adsorption capacity of 468.3 mg/g (pH = 5). In addition, the factors affecting uranium adsorption process were investigated by a batch of adsorption tests under different adsorption conditions. ZIF-90-AO displayed good selectivity to UO22+ in the solution containing multiple co-existing ions and good regeneration property. More importantly, ZIF-90-AO showed excellent antimicrobial property against both E. coli and S. aureus. Therefore, ZIF-90-AO is a U-adsorbent with great application value for removing U (VI) from wastewater due to the high U (VI) adsorption capacity in weak acid condition and good anti-biofouling properties.


Assuntos
Urânio , Adsorção , Antibacterianos , Escherichia coli , Nitrilas , Oximas , Staphylococcus aureus , Urânio/análise
2.
Chemosphere ; 287(Pt 2): 132137, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34496335

RESUMO

Uranium extraction and recovery play a critical role in guaranteeing the sustainable nuclear energy supply and protecting the environmental safety. The ideal uranium sorbents possess high adsorption capacity, excellent selectivity and reusability, as well as outstanding antimicrobial property, which are greatly desired for the real application of uranium extraction from seawater. To address this challenge, a novel magnetic core-shell adsorbent was designed and fabricated by a facile method. The obtained amidoximed Fe3O4@TiO2 particles (Fe3O4@TiO2-AO) achieved equilibrium in 2 h and the maximum adsorption capacity calculated from Langmuir model is 217.0 mg/g. The adsorption kinetics followed the pseudo-second-order model. Meanwhile, the Fe3O4@TiO2-AO exhibited great selectivity when competitive metal ions and anions coexisted. In addition, the magnetic Fe3O4@TiO2-AO could be conveniently separated and collected by an external magnetic field, the regeneration efficiency maintained at 78.5% even after ten adsorption-desorption cycles. In natural seawater, the uranium uptake reached 87.5 µg/g in 33 days. Furthermore, the TiO2 contained adsorbent showed effective photo induced bactericidal properties against both E. coli and S. aureus. The Fe3O4@TiO2-AO with great U(VI) adsorption performance is highly promising in uranium extraction and reclamation.


Assuntos
Urânio , Adsorção , Antibacterianos , Escherichia coli , Oximas , Água do Mar , Staphylococcus aureus , Titânio
3.
J Colloid Interface Sci ; 607(Pt 1): 890-899, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34536942

RESUMO

Polymers of intrinsic microporosity (PIM-1) has demonstrated great potential in adsorption and separation fields. In this study, PIM-1 was structured into an applicable and efficient adsorbent using a facile way. PIM-1 was first modified by amidoxime, and then the amidoxime modified PIM-1 (AOPIM-1) was mingled into alginate (Alg) hydrogel to obtain composite hydrogel beads. The AOPIM-1/Alg composite beads were further employed for removal of malachite green (MG) from aqueous solution and the effects of doped ratio, adsorbent dosage, contact time, and initial dye concentration on the MG adsorption performance were systematically investigated. The MG adsorption capacity of pure Alg beads was substantially enhanced after incorporating AOPIM-1. Furthermore, isothermal, kinetic and thermodynamic studies were performed to explore the fundamental adsorption behavior. Both Freundlich isotherm and Langmuir isotherm models can fit the adsorption isotherm data well, and the adsorption kinetics is well described by Pseudo-second-order. The adsorption process is feasible, spontaneous and endothermic. In addition, mixed dyes adsorption measurements indicate that AOPIM-1/Alg beads are highly selective to adsorb cationic dyes from anionic/cationic mixed dyes solution. The regeneration test shows that above 90% of the adsorption capacity of the composite beads can be maintained after 10 cycles of MG adsorption/desorption. These findings point that AOPIM-1/Alg composite hydrogel beads are an efficient, up-and-coming and recyclable adsorbent for cationic dyes adsorption from aqueous solution.


Assuntos
Alginatos , Poluentes Químicos da Água , Adsorção , Corantes , Hidrogéis , Oximas , Polímeros
4.
Acta Medica (Hradec Kralove) ; 64(3): 145-152, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34779379

RESUMO

AIM: The comparison of neuroprotective and central reactivating effects of the oxime K870 in combination with atropine with the efficacy of standard antidotal treatment in tabun-poisoned rats. METHODS: The neuroprotective effects of antidotal treatment were determined in rats poisoned with tabun at a sublethal dose using a functional observational battery 2 h and 24 h after tabun administration, the tabun-induced brain damage was investigated by the histopathological evaluation and central reactivating effects of oximes was evaluated by the determination of acetylcholinesterase activity in the brain using a standard spectrophotometric method. RESULTS: The central reactivating efficacy of a newly developed oxime K870 roughly corresponds to the central reactivating efficacy of pralidoxime while the ability of the oxime HI-6 to reactivate tabun-inhibited acetylcholinesterase in the brain was negligible. The ability of the oxime K870 to decrease tabun-induced acute neurotoxicity was slightly higher than that of pralidoxime and similar to the oxime HI-6. These results roughly correspond to the histopathological evaluation of tabun-induced brain damage. CONCLUSION: The newly synthesized oxime K870 is not a suitable replacement for commonly used oximes in the antidotal treatment of acute tabun poisonings because its neuroprotective efficacy is only slightly higher or similar compared to studied currently used oximes.


Assuntos
Substâncias para a Guerra Química , Reativadores da Colinesterase , Organofosfatos , Oximas , Venenos , Compostos de Piridínio , Acetilcolinesterase , Animais , Antídotos/farmacologia , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/farmacologia , Reativadores da Colinesterase/farmacologia , Oximas/farmacologia , Compostos de Pralidoxima , Compostos de Piridínio/farmacologia , Ratos , Ratos Wistar
5.
Molecules ; 26(21)2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34771067

RESUMO

Gastrointestinal tract infection caused by Helicobacter pylori is a common virulent disease found worldwide, and the infection rate is much higher in developing countries than in developed ones. In the pathogenesis of H. pylori in the gastrointestinal tract, the secretion of the urease enzyme plays a major role. Therefore, inhibition of urease is a better approach against H. pylori infection. In the present study, a series of syn and anti isomers of N-substituted indole-3-carbaldehyde oxime derivatives was synthesized via Schiff base reaction of appropriate carbaldehyde derivatives with hydroxylamine hydrochloride. The in vitro urease inhibitory activities of those derivatives were evaluated against that of Macrotyloma uniflorum urease using the modified Berthelot reaction. Out of the tested compounds, compound 8 (IC50 = 0.0516 ± 0.0035 mM) and compound 9 (IC50 = 0.0345 ± 0.0008 mM) were identified as the derivatives with potent urease inhibitory activity with compared to thiourea (IC50 = 0.2387 ± 0.0048 mM). Additionally, in silico studies for all oxime compounds were performed to investigate the binding interactions with the active site of the urease enzyme compared to thiourea. Furthermore, the drug-likeness of the synthesized oxime compounds was also predicted.


Assuntos
Antibacterianos/farmacologia , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/efeitos dos fármacos , Indóis/farmacologia , Oximas/farmacologia , Urease/antagonistas & inibidores , Antibacterianos/síntese química , Antibacterianos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Helicobacter pylori/enzimologia , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Oximas/síntese química , Oximas/química , Estereoisomerismo , Urease/metabolismo
6.
Chem Biol Interact ; 350: 109654, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34634268

RESUMO

Since their use during the First World War, Blister agents have posed a major threat to the individuals and have caused around two million casualties. Major incidents occurred not only due to their use as chemical warfare agents but also because of occupational hazards. Therefore, a clear understanding of these agents and their mode of action is essential to develop effective decontamination and therapeutic strategies. The blister agents have been categorised on the basis of their chemistry and the biological interactions that entail post contamination. These compounds have been known to majorly cause blisters/bullae along with alkylation of the contaminated DNA. However, due to the high toxicity and restricted use, very little research has been conducted and a lot remains to be clearly understood about these compounds. Various decontamination solutions and detection technologies have been developed, which have proven to be effective for their timely mitigation. But a major hurdle seems to be the lack of proper understanding of the toxicological mechanism of action of these compounds. Current review is about the detailed and updated information on physical, chemical and biological aspects of various blister agents. It also illustrates the mechanism of their action, toxicological effects, detection technologies and possible decontamination strategies.


Assuntos
Vesícula/induzido quimicamente , Substâncias para a Guerra Química/química , Substâncias para a Guerra Química/toxicidade , Descontaminação/métodos , Alquilantes/química , Alquilantes/toxicidade , Arsenicais/efeitos adversos , Arsenicais/química , Vesícula/terapia , Substâncias para a Guerra Química/classificação , Olho/efeitos dos fármacos , Humanos , Pulmão/efeitos dos fármacos , Modelos Biológicos , Compostos de Mostarda/química , Compostos de Mostarda/toxicidade , Oximas/química , Oximas/toxicidade , Fosgênio/química , Fosgênio/toxicidade , Pele/efeitos dos fármacos
7.
Value Health Reg Issues ; 26: 182-190, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34673349

RESUMO

OBJECTIVES: Advanced melanoma accounts for 4% of malignant skin tumors, and approximately 80% of deaths are attributed to it. The most frequent mutation of the RAF gene is BRAFV600, which has been associated with a worse prognosis. The objective of the research was to evaluate the cost-effectiveness of the combined regimen of dabrafenib plus trametinib (D + T) compared with other targeted therapies, immunotherapy, and dacarbazine for the treatment of unresectable/metastatic melanoma with BRAFV600 mutation from the perspective of the Colombian health system. METHODS: A partitioned survival model with 3 states (progression-free survival, progression, and death) was used to evaluate the cost-effectiveness for a time horizon of 20 years. Owing to the perspective of the analysis, only direct medical costs were taken into account. The efficacy of the evaluated treatment and the comparators were measured in terms of overall survival and progression-free survival. All costs were expressed in Colombian pesos as of 2018, and outcomes and costs were discounted at 5% annually. Two analysis scenarios were considered, one in which only monitoring and follow-up costs were included in the progression phase and another in which costs of acquisition of possible treatment sequences were also included. RESULTS: In the first scenario (without postprogression medication costs), the combined D + T regimen was a dominant alternative to vemurafenib + cobimetinib but was not a cost-effective option compared with vemurafenib, nivolumab, ipilimumab, nivolumab + ipilimumab, pembrolizumab, and dacarbazine. In the second scenario (with drug costs in postprogression), D + T was dominant compared with vemurafenib + cobimetinib and cost-effective compared with nivolumab and pembrolizumab. Compared with other schemes, the incremental cost-effectiveness ratio was above the threshold of 3 gross domestic product per capita. Probabilistic sensitivity analyses showed that a willingness-to-pay threshold of Col$56 484 300 (US$19 108) per quality-adjusted life-year would not be reached at the current price of schema in Colombia. CONCLUSIONS: The combined scheme could be a cost-effective and even a cost-saving alternative to vemurafenib + cobimetinib, nivolumab, and pembrolizumab if the costs associated with the use of other medications are taken into account after progression to the first line of treatment. Compared with the other comparators, it produces a greater number of quality-adjusted life-years, but the incremental cost-effectiveness ratio is above that of the willingness to pay.


Assuntos
Dacarbazina , Melanoma , Colômbia , Análise Custo-Benefício , Humanos , Imidazóis , Imunoterapia , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Oximas , Piridonas , Pirimidinonas
8.
J Hematol Oncol ; 14(1): 143, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34496925

RESUMO

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours' samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.


Assuntos
Adenomioepitelioma/genética , Neoplasias da Mama/genética , Mutação Puntual , Proteínas Proto-Oncogênicas p21(ras)/genética , Adenomioepitelioma/tratamento farmacológico , Adenomioepitelioma/patologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Mama/efeitos dos fármacos , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/uso terapêutico , Pessoa de Meia-Idade , Oximas/uso terapêutico , Mutação Puntual/efeitos dos fármacos , Inibidores de Proteínas Quinases/uso terapêutico , Piridonas/uso terapêutico , Pirimidinonas/uso terapêutico
9.
Molecules ; 26(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34500612

RESUMO

Red cabbage (Brassica oleracea L. var. capitata) continues to receive increasing attention on its health-promoting properties because of its high glucosinolate content. Glucosinolates are an unstable active substance; however, there are few studies on their changes in different cooking processes. In this study, we investigated the effects of processing methods (boiling, steaming, microwave heating, frying, stir-frying) and boiling time on glucosinolates in red cabbage. Ten glucosinolates, including 4-methoxyglucobrassicin, neoglucobrassicin, glucoalyssin, glucobrassicin, glucoraphanin, glucoiberin, progoitrin, gluconapin and sinigrin, in red cabbage were detected. Decreases of 32.36%, 24.83%, 25.27%, 81.11% and 84.29% for total glucosinolates were observed after boiling, microwaving, steaming, frying and stir-frying. Indole glucosinolates were more efficiently lost compared to aliphatic glucosinolates after boiling, while microwaving, steaming, frying and stir-frying also resulted in a greater reduction in indole glucosinolates than aliphatic glucosinolates. Glucoalyssin, glucoerucin and sinigrin were more thermal sensitive than other glucosinolates. It was confirmed that microwaving and steaming retained higher levels of glucosinolates than other methods and may be better for cooking red cabbage.


Assuntos
Brassica/química , Glucosinolatos/química , Cromatografia Líquida/métodos , Culinária/métodos , Glucose/análogos & derivados , Glucose/química , Imidoésteres/química , Indóis/química , Micro-Ondas , Oximas/química , Sulfóxidos/química , Espectrometria de Massas em Tandem/métodos
10.
PLoS One ; 16(9): e0257206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34506566

RESUMO

Dengue virus (DENV) encodes a unique protease (NS3/NS2B) essential for its maturation and infectivity and, it has become a key target for anti-viral drug design to treat dengue and other flavivirus related infections. Present investigation established that some of the drug molecules currently used mainly in cancer treatment are susceptible to bind non-active site (allosteric site/ cavity) of the NS3 protease enzyme of dengue virus. Computational screening and molecular docking analysis found that dabrafenib, idelalisib and nintedanib can bind at the allosteric site of the enzyme. The binding of the molecules to the allosteric site found to be stabilized via pi-cation and hydrophobic interactions, hydrogen-bond formation and π-stacking interaction with the molecules. Several interacting residues of the enzyme were common in all the five serotypes. However, the interaction/stabilizing forces were not uniformly distributed; the π-stacking was dominated with DENV3 proteases, whereas, a charged/ionic interaction was the major force behind interaction with DENV2 type proteases. In the allosteric cavity of protease from DENV1, the residues Lys73, Lys74, Thr118, Glu120, Val123, Asn152 and Ala164 were involved in active interaction with the three molecules (dabrafenib, idelalisib and nintedanib). Molecular dynamics (MD) analysis further revealed that the molecules on binding to NS3 protease caused significant changes in structural fluctuation and gained enhanced stability. Most importantly, the binding of the molecules effectively perturbed the protein conformation. These changes in the protein conformation and dynamics could generate allosteric modulation and thus may attenuate/alter the NS3 protease functionality and mobility at the active site. Experimental studies may strengthen the notion whether the binding reduce/enhance the catalytic activity of the enzyme, however, it is beyond the scope of this study.


Assuntos
Imidazóis/farmacologia , Indóis/farmacologia , Oximas/farmacologia , Purinas/farmacologia , Quinazolinonas/farmacologia , Sequência de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Imidazóis/química , Indóis/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Oximas/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Estrutura Secundária de Proteína , Purinas/química , Quinazolinonas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química
11.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502172

RESUMO

Vascular calcification associated with high plasma phosphate (Pi) level is a frequent complication of hyperglycemia, diabetes mellitus, and chronic kidney disease. BGP-15 is an emerging anti-diabetic drug candidate. This study was aimed to explore whether BGP-15 inhibits high Pi-induced calcification of human vascular smooth muscle cells (VSMCs) under normal glucose (NG) and high glucose (HG) conditions. Exposure of VSMCs to Pi resulted in accumulation of extracellular calcium, elevated cellular Pi uptake and intracellular pyruvate dehydrogenase kinase-4 (PDK-4) level, loss of smooth muscle cell markers (ACTA, TAGLN), and enhanced osteochondrogenic gene expression (KLF-5, Msx-2, Sp7, BMP-2). Increased Annexin A2 and decreased matrix Gla protein (MGP) content were found in extracellular vesicles (EVs). The HG condition markedly aggravated Pi-induced VSMC calcification. BGP-15 inhibited Pi uptake and PDK-4 expression that was accompanied by the decreased nuclear translocation of KLF-5, Msx-2, Sp7, retained VSMC markers (ACTA, TAGLN), and decreased BMP-2 in both NG and HG conditions. EVs exhibited increased MGP content and decreased Annexin A2. Importantly, BGP-15 prevented the deposition of calcium in the extracellular matrix. In conclusion, BGP-15 inhibits Pi-induced osteochondrogenic phenotypic switch and mineralization of VSMCs in vitro that make BGP-15 an ideal candidate to attenuate both diabetic and non-diabetic vascular calcification.


Assuntos
Hiperglicemia/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oximas/farmacologia , Fosfatos/metabolismo , Piperidinas/farmacologia , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Biomarcadores , Glicemia , Células Cultivadas , Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Hiperglicemia/sangue , Osteoblastos/metabolismo , Fosfatos/efeitos adversos , Calcificação Vascular/tratamento farmacológico
12.
J Pharm Biomed Anal ; 206: 114351, 2021 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-34509659

RESUMO

Dabrafenib (Tafinlar) is used for the treatment of patients with BRAF V600 mutation positive unresectable or metastatic melanoma. Forced degradation study of the drug product and drug substance is very much important in drug development and drug discovery to establish the intrinsic stability and understand its behaviors towards different stress conditions. In the current study, compressive stress testing of dabrafenib has been performed as per the recommendation of ICH guidelines to identify and characterize all major degradation products of dabrafenib (DPD) formed. Drug substances were exposed to different stressed conditions as per ICH recommendations. The present study observed that the dabrafenib drug substance is very much sensitive when exposed to oxidative degradation conditions at 80 °C temperature conditions and also sensitive to photolytic degradation conditions. Dabrafenib is stable when treated in acidic, alkaline, neutral and thermal degradation environments as there is no degradation observed in signification percentage under these stressed conditions. The best separation of eight degradation products and dabrafenib drug substance was obtained in Waters BEH (Ethylene Bridge Hybrid) C-18 column (1.7 µm, 100 mm × 2.1 mm) having mobile phase composed of Formic acid (0.1%) and methanol as Eluent A and Eluent B respectively using 225 nm wavelengths. The volume of injection (5 µL) and flow rate (0.3 mL/min) was set throughout the study. Dabrafenib is highly unstable to oxidative stressed conditions as five major degradation products (DPD-II, DPD-III, DPD-IV, DPD-V and DPD-VII) were obtained when exposed to hydrogen peroxide. When dabrafenib is treated under photolytic degradation conditions, three major DPs were formed (DPD-I, DPD-VI and DP-VIII). These DPs were further identified and characterized on sophisticated HRMS/MS/TOF technique for accurate mass measurement. Characterization of all the degradation products was carried out in the ESI positive mode of ionization. The establishment of the degradation pathway of drug substance and fragmentation pathway of DPs were explained in the present study which was never reported in any literature.


Assuntos
Estabilidade de Medicamentos , Imidazóis/química , Oximas/química , Cromatografia Líquida , Hidrólise , Oxirredução , Fotólise , Espectrometria de Massas em Tandem
13.
Macromol Rapid Commun ; 42(22): e2100478, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34519386

RESUMO

A new sequential post-polymerization modification route has been developed for the synthesis of multifunctional polymers from a simple aldehyde polymer. In the first modification step, a template polymer derived from the radical polymerization of 4-vinyl benzaldehyde undergoes Rh-catalyzed hydroacylation with alkenes to furnish a group of ketone polymers. In the second modification step, Schiff base formation with alkoxy ammonium salts introduces a second group-an oxime functionality. Both the steps are highly efficient, introducing evenly distributed dual functionalities at the same position.


Assuntos
Aldeídos , Cetonas , Oximas , Polimerização , Polímeros
14.
Anal Methods ; 13(39): 4634-4641, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34542114

RESUMO

In this paper, the catalytic activity of CeO2 NPs toward oxime oxidation was adopted for the first time to develop an electrochemical sensor with improved sensitivity toward the direct detection of organophosphorus pesticides (OPs) without electrochemical redox activity. To enhance the conductivity of the sensor, CeO2 NPs together with multi-walled carbon nanotubes (MWCNTs) were deposited onto a bare glassy carbon electrode (GCE) by the simple method of drop-casting. The electrochemical properties of the as-prepared sensor were evaluated in K3[Fe(CN)6] solution and the oxidation behavior of pralidoxime (PAM) chloride on the electrodes was characterized by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The results show that the modification of CeO2 onto the electrode not only increases the electroactive area of the electrode but also significantly increases the peak current of PAM chloride oxidation, which confirms that CeO2 has an electrocatalytic effect toward oxime oxidation. To evaluate the sensitivity of the as-fabricated sensor, the inhibition rate of PAM chloride peak current was tested in PAM chloride solution containing different concentrations of chlorpyrifos, which shows a very small detection limit of 2.5 × 10-9 M. In addition, the sensor successfully achieved a convenient and sensitive determination of OPs in vegetable extracts.


Assuntos
Nanotubos de Carbono , Praguicidas , Eletrodos , Compostos Organofosforados , Oximas
15.
Colloids Surf B Biointerfaces ; 208: 112093, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34482192

RESUMO

The transmembrane proteins, CD47 and signal-regulatory protein α are overexpressed in cancer cells and macrophages, respectively, and facilitate the escape of cancer cells from macrophage-mediated phagocytosis. The immunomodulatory and targeting properties of CD47, the chemotherapeutic effects of dabrafenib (D), and the anti-programmed death-1 antibodies (PD-1) pave the way for effective chemoimmunomodulation-mediated anticancer combination therapy. In this study, CD47-conjugated, D-loaded human serum albumin (HSA) nanosystems were fabricated by modified nanoparticle albumin-bound technology. Cis-aconityl-PEG-maleimide (CA), an acid-labile linker, was used to conjugate D@HSA and CD47; the resultant CD47-CA@D@HSA exhibited tumor-specificity through receptor targeting, as well as preferential cleavage and drug release in the acidic tumor microenvironment (pH 5) compared to normal physiological pH conditions (pH 6.5, 7.4). The successful preparation of nanosized (∼220 nm), narrowly dispersed (∼0.13) CD47-CA@D@HSA was proven by physicochemical characterization. In vitro and in vivo internalization, accumulation, cytotoxicity, and apoptosis were observed to be higher with CD47-conjugated nanoconstructs, than with free D or non-targeted nanoconstructs. CD47-CA@D@HSA was found to promote the infiltration of cytotoxic T cells and tumor-associated macrophages into tumors and improve in vivo tumor inhibition. Administration in combination with PD-1 further improved antitumor efficacy by promoting immune responses that blocked the immune checkpoint. No signs of toxicity were seen in mice treated with the nanoconstructs; the formulation was, therefore, thought to be biocompatible and as having potential for clinical use. The targeted chemoimmunomodulation achieved by this combination therapy was found to combat major immunosuppressive facets, making it a viable candidate for use in the treatment of cancer.


Assuntos
Antígeno CD47 , Albumina Sérica Humana , Animais , Imidazóis/farmacologia , Camundongos , Oximas , Fagocitose
16.
Enzyme Microb Technol ; 150: 109883, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34489036

RESUMO

Aromatic nitriles are important structural motifs that frequently existed in pharmaceutical drugs. Due to the convenient synthesis of aldoximes from aldehydes, the dehydration of aldoximes to corresponding nitriles by aldoxime dehydratases (Oxds) is considered as a safe and robust enzymatic production route. Although the Oxd genes are widely distributed in microbial kingdom, so far less than ten Oxds were expressed and further characterized. In this study, we found 26 predicted putative Oxd genes from the GenBank database using a genome mining strategy. The Oxd gene from Pseudomonas putida F1 was cloned and functionally expressed in Escherichia coli BL21 (DE3). The amino acid sequence of OxdF1 shows high identities of 33∼85 % to other characterized Oxds, and contained a ferrous heme as the catalytic site. The optimum reaction pH and temperature of recombinant OxdF1 were 7.0 and 35 °C, respectively. OxdF1 was stable in pH 7.0 potassium phosphate buffer at 30 °C, and its half-life was approximately 3.8 h. OxdF1 can efficiently dehydrate aromatic and heterocyclic aldoximes to nitriles, such as 2-bromobenzaldoxime, 2-chloro-6-fluorobenzaldoxime, thiophene-2-carboxaldoxime, and pyridine-3-aldoxime. Therefore, the recombinant OxdF1 shows a potential application in the cyanide-free synthesis of aromatic nitriles.


Assuntos
Heme , Nitrilas , Pseudomonas putida/enzimologia , Hidroliases/genética , Oximas
17.
Curr Oncol ; 28(5): 3537-3553, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34590600

RESUMO

The combination of dabrafenib and trametinib is a well-established treatment for BRAF-mutated melanoma. However, the effectiveness of this approach may be hindered by the development of treatment-related pyrexia syndrome, which occurs in at least 50% of treated patients. Without appropriate intervention, pyrexia syndrome has the potential to worsen and can result in hypotension secondary to dehydration and associated organ-related complications. Furthermore, premature treatment discontinuation may result in a reduction in progression-free and overall survival. Despite existing guidance, there is still a wide variety of therapeutic approaches suggested in the literature for both the definition and management of dabrafenib and trametinib-related pyrexia. This is reflected in the practice variation of its prevention and treatment within and between Canadian cancer centres. A Canadian working group was formed and consensus statements were constructed based on evidence and finalised through a two-round modified Delphi approach. The statements led to the development of a pyrexia treatment algorithm that can easily be applied in routine practice. The Canadian working group consensus statements serve to provide practical guidance for the management of dabrafenib and trametinib-related pyrexia, hopefully leading to reduced discontinuation rates, and ultimately improve patients' quality of life and cancer-related outcomes.


Assuntos
Proteínas Proto-Oncogênicas B-raf , Qualidade de Vida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Canadá , Consenso , Febre/induzido quimicamente , Febre/tratamento farmacológico , Humanos , Imidazóis , Mutação , Oximas , Proteínas Proto-Oncogênicas B-raf/genética , Piridonas , Pirimidinonas
18.
Molecules ; 26(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34577159

RESUMO

c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs.


Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Oximas/química , Oximas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Disponibilidade Biológica , Linhagem Celular , Humanos , Interleucina-6/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Lipopolissacarídeos/toxicidade , Monócitos/efeitos dos fármacos , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Quinoxalinas/química , Quinoxalinas/farmacologia
19.
Anal Chim Acta ; 1181: 338934, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556216

RESUMO

Nickel isotope ratios have traditionally been used as an important tracer in cosmochemistry, and recently, it has gained attention in geochemistry, biochemistry, and environmental sciences with the development of MC-ICP-MS. Purification of Ni before isotope measurement is mandatory for obtaining precise data, which has been commonly achieved with ion-exchange chromatography, employing dimethylglyoxime (DMG) as a chelating agent for Ni. However, it has been pointed out that the use of DMG can adversely affect the isotope measurement due to insufficient Ni recovery and mass bias during measurement caused by the remaining DMG. Ni isolation procedures without the usage of DMG were innovated, but they have disadvantages such as the necessity of complex separation methods, high Ni blank, and matrix-dependent Ni recovery. Here, we present a simple Ni isolation procedure without using DMG but with the aid of oxalic acid along with common inorganic acids, achieving near-complete recovery of Ni with low blanks [0.7 ± 0.3 ng (2SD, n = 4)] only using three ion exchange column steps. To validate our method and strengthen the Ni isotope database of reference materials, 60Ni/58Ni of 20 geological reference materials, covering wide matrix compositions, were measured by MC-ICP-MS using the double-spike method. The results have shown that high recovery of Ni, independent of the sample matrix elements was achieved (98 ± 4%) and the 60Ni/58Ni was measured with a 2SD of 0.006-0.084‰ from samples containing 100-200 ng Ni.


Assuntos
Isótopos , Níquel , Espectrometria de Massas , Oximas
20.
J Org Chem ; 86(17): 11399-11406, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34365792

RESUMO

We report the visible-light-promoted selenocyanation of cyclobutanone oxime esters using potassium selenocyanate in the presence of a fac-Ir(ppy)3 catalyst for the first time. Because of the mild conditions employed and use of readily accessible potassium selenocyanate, this method is an effective and green strategy for the synthesis of cyano and selenocyano bifunctional substituted alkanes.


Assuntos
Ésteres , Oximas , Cianatos , Potássio , Compostos de Selênio
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