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1.
Environ Monit Assess ; 196(7): 605, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38856803

RESUMO

Petroleum hydrocarbons (PHCs) are produced from industrial discharges, storage leakages, accidental spills, and operational failures. The hazardous nature of PHCs causes serious health risks and threatens the entire aquatic habitat. In this research work, the investigation of the removal of total petroleum hydrocarbons (TPHs) from the contaminated water is carried out utilizing a novel hypercross-linked resin, MAICY, which is generated by condensation of commercially available precursors. The chemical structures of MAICY have been examined extensively by FESEM, FT-IR, solid (CP-MAS) 13C-NMR, and TGA. A comprehensive analysis for adsorption parameters of TPHs has been performed, and different models such as Langmuir and Freundlich isotherms have been employed where the Freundlich isotherm was found to be the best fit for removal of THPs (R2= 0.9991). The results revealed that the performance of MAICY for the adsorption of TPHs from contaminated water gives a maximum adsorption capacity (qe) of 146 mg.g-1. The results of various parameters hinted that the contact time (0.25-4 h), the dosage of adsorbent (0.17 g/L), pH (7), and concentration of TPHs (26.5 mg/L) have controlled the overall adsorptive performance. Moreover, the kinetic data of qe(expt.) and qe(calc.) for adsorption of TPHs disclosed the regression values (R2) for pseudo-first order (R2= 0.9921) and pseudo-second order (R2= 0.9891). Additionally, based on CHI factor (X2) error estimations, the data was shown to be more consistent with pseudo-first-order kinetics. Moreover, MAICY demonstrated excellent reusability and recycling properties for up to four consecutive adsorption-desorption cycles.


Assuntos
Hidrocarbonetos , Petróleo , Triazinas , Poluentes Químicos da Água , Poluentes Químicos da Água/análise , Adsorção , Petróleo/análise , Triazinas/química , Triazinas/análise , Cinética
2.
Cell Commun Signal ; 22(1): 324, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38867255

RESUMO

BACKGROUND: KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions. METHODS: Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model. RESULTS: Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression. CONCLUSIONS: We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Mutação , Omeprazol , Proteínas Proto-Oncogênicas c-met , Proteínas Proto-Oncogênicas p21(ras) , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Linhagem Celular Tumoral , Animais , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Omeprazol/farmacologia , Omeprazol/uso terapêutico , Camundongos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Nus , Pirimidinonas/farmacologia , Pirimidinonas/uso terapêutico , Feminino , Triazinas/farmacologia , Triazinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Piperazinas , Piperidinas , Piridazinas , Piridonas
3.
J Zoo Wildl Med ; 55(2): 313-321, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38875188

RESUMO

High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens (Gallus domesticus, order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens (n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.


Assuntos
Antivirais , Galinhas , Dibenzotiepinas , Morfolinas , Piridonas , Triazinas , Animais , Triazinas/administração & dosagem , Dibenzotiepinas/administração & dosagem , Administração Oral , Antivirais/administração & dosagem , Antivirais/farmacologia , Morfolinas/administração & dosagem , Morfolinas/farmacologia , Piridonas/administração & dosagem , Piridonas/farmacologia , Piridinas/administração & dosagem , Tiepinas/administração & dosagem , Tiepinas/farmacologia , Masculino , Influenza Aviária/tratamento farmacológico , Feminino , Oxazinas , Hidroxibutiratos/administração & dosagem
4.
Anal Chim Acta ; 1314: 342796, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38876515

RESUMO

BACKGROUND: Excessive pesticide residues in agricultural products could accumulate in organisms through the food chain, causing potential harm to human health. The investigation of dissipation kinetics and residues of pesticides in crops is crucial for the scientific application of pesticides and the mitigation of their adverse effects on human health. In vivo solid-phase microextraction (in vivo SPME) has unique advantages, but the research on field plants is still lacking and the quantitative correction methods need to be further developed. RESULTS: A method combining in vivo solid-phase microextraction with ultra-performance liquid chromatography-tandem mass spectrometry (in vivo SPME-UPLC-MS/MS) was developed to monitor the presence of acetamiprid, cyromazine, thiamethoxam and imidacloprid in cowpea fruits grown in the field. The sampling rates (Rs) were determined using both in vitro SPME in homogenized cowpea samples and in vivo SPME in intact cowpea fruit samples. The in vivo-Rs values were significantly higher than the in vitro-Rs for the same analyte, which were used for in vivo SPME correction. The accuracy of this method was confirmed by comparison with a QuEChERS-based approach and subsequently applied to trace pesticide residues in field-grown cowpea fruits. The residual concentrations of each pesticide positively correlated with application doses. After 7 days of application at two different doses, all of the pesticides had residual concentrations below China's maximum residue limits. Both experimental data and predictions indicated that a safe preharvest interval for these pesticides is 7 days; however, if the European Union standards are to be met, a safe preharvest interval for cyromazine should be at least 13 days. SIGNIFICANCE: This study highlights the advantages of in vivo SPME for simultaneous analysis and tracking of multiple pesticides in crops under field conditions. This technique is environmentally friendly, minimally invasive, highly sensitive, accurate, rapid, user-friendly, cost-effective, and capable of providing precise and timely data for long-term pesticide surveillance. Consequently, it furnishes valuable insights to guide the safe utilization of pesticides in agricultural production.


Assuntos
Neonicotinoides , Resíduos de Praguicidas , Microextração em Fase Sólida , Espectrometria de Massas em Tandem , Triazinas , Vigna , Vigna/química , Espectrometria de Massas em Tandem/métodos , Neonicotinoides/análise , Microextração em Fase Sólida/métodos , Cromatografia Líquida de Alta Pressão/métodos , Triazinas/análise , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/isolamento & purificação , Frutas/química
5.
Anal Chim Acta ; 1312: 342780, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38834272

RESUMO

BACKGROUND: The convenient preparation and application of functionalized organic-inorganic hybrid monolithic materials have obtained substantial interest in the pretreatment of complex samples by solid-phase extraction (SPE). Compared to the in-tube solid-phase microextraction in fused-silica capillaries, micro SPE in plastic pipette tips have fascinating merits for the easily operated enrichment of trace target analytes from biological samples. However, the poor compatibility of organic-inorganic hybrid monoliths with plastics leads to the rare appearance of commercial hybrid monolithic pipette tips (HMPTs). Therefore, how to synthesize the organic-inorganic hybrid monolithic materials with better extraction performance in plastic pipette tips becomes a challenge. RESULTS: We develop a facile and cheap strategy to immobilize organic-inorganic hybrid monoliths in pipette tips. Melamine sponge was employed as the supporting skeleton to in situ assemble amine- and thiol-bifunctionalized hybrid monolithic material via "one pot" in a pipette tip, and gold nanoparticles (GNPs) and thiol-modified aptamer against human α-thrombin were sequentially attached to the hybrid monolith within the HMPTs. The average coverage density of the aptamer with GNPs as an intermediary reached as high as 818.5 pmol µL-1. The enriched thrombin concentration was determined by a sensitive enzymatic chromogenic assay with the limit of detection of 2 nM. The extraction recovery of thrombin at 10 nM in human serum was 86.1 % with a relative standard deviation of 6.1 %. This proposed protocol has been applied to the enrichment and determination of thrombin in real serum sample with strong anti-interference ability, low limit of detection and high recovery. SIGNIFICANCE: The amine- and thiol-bifunctionalized HMPTs prepared with sponge as the skeleton frame provided a novel substrate material to decorate aptamers for efficient enrichment of proteins. This enlightens us that we can take advantage of the tunability of sponge assisted HMPTs to produce and tailor a variety of micro SPE pipette tips for broader applications on the analysis of trace targets in complex biological, clinic and environmental samples.


Assuntos
Aptâmeros de Nucleotídeos , Trombina , Triazinas , Triazinas/química , Triazinas/isolamento & purificação , Aptâmeros de Nucleotídeos/química , Humanos , Trombina/análise , Trombina/isolamento & purificação , Ouro/química , Nanopartículas Metálicas/química , Extração em Fase Sólida/métodos
6.
Mol Cancer ; 23(1): 123, 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38849845

RESUMO

BACKGROUND: Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS: To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS: Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS: We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.


Assuntos
Neoplasias Encefálicas , Glioma , Proteínas Proto-Oncogênicas c-met , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Glioma/patologia , Glioma/tratamento farmacológico , Glioma/genética , Glioma/terapia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Camundongos , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Linhagem Celular Tumoral , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Feminino , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Crizotinibe/farmacologia , Crizotinibe/uso terapêutico , Modelos Animais de Doenças , Criança , Gradação de Tumores , Anilidas/farmacologia , Imidazóis , Triazinas
7.
J Chromatogr A ; 1727: 464978, 2024 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-38788401

RESUMO

A novel azo-linked porous organic polymer (AL-POP) was synthesized from caffeic acid and benzidine via an azo-coupling reaction and characterized by FTIR, SEM-EDS, BET, TGA, XRD and zeta potential analysis. AL-POPs were incorporated into melamine sponges and used for pipette tip micro solid-phase extraction (PT-MSPE) of six types of B vitamins (including thiamine, riboflavin, nicotinamide, pyridoxine, folic acid, and cyanocobalamin). After extraction, the samples were analyzed using high performance liquid chromatography-diode array detection (HPLC-DAD) system. The effect of AL-POP composition on the extraction efficiency (EE) of vitamins was investigated and benzidine to caffeic acid mol ratio of 1.5, 3.35 mmol of NaNO2, and reaction time of 8 h were selected as optimum conditions. The efficiency of the extraction process was improved by optimizing various parameters such as the amount of sorbent, pH and ionic strength of the sample, sample volume, number of sorption and desorption cycles, type of wash solvent, and type and volume of eluent solvent. Linearity (R2≥0.9987), Limit of detection (LOD) (11.88-18.97 ng/mL), limit of quantification (LOQ) (39.62-63.23 ng/mL), and enrichment factor (EF) (1.27-4.31) were obtained using calibration curves plotted under optimum conditions. Recovery values of these six B vitamins in the spiked multivitamin syrup samples varied from 80.01% to 108.35%, with a relative standard deviation (RSD) below 5.44%. Eventually, the optimized method was successfully used to extract and quantify the B vitamins in multivitamin syrup and non-alcoholic beer.


Assuntos
Limite de Detecção , Triazinas , Complexo Vitamínico B , Triazinas/análise , Triazinas/química , Triazinas/isolamento & purificação , Porosidade , Cromatografia Líquida de Alta Pressão/métodos , Complexo Vitamínico B/análise , Complexo Vitamínico B/química , Complexo Vitamínico B/isolamento & purificação , Adsorção , Polímeros/química , Compostos Azo/análise , Compostos Azo/química , Compostos Azo/isolamento & purificação , Microextração em Fase Sólida/métodos , Extração em Fase Sólida/métodos , Concentração de Íons de Hidrogênio
8.
Food Chem ; 453: 139652, 2024 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-38761737

RESUMO

Diclazuril (DIC) is a broad-spectrum anti-coccidiosis drug of the triazine class, widely used in poultry farming. The overuse of DIC may lead to its accumulation in animal bodies, which may enter the food chain and threaten human health. In this work, we fabricated a stable Eu3+-doped UiO-66 fluorescence sensor (EuUHIPA-30) for the sensitive detection of DIC. Among 20 veterinary drugs, the fluorescence of EuUHIPA-30 selectively responds to DIC, with a low detection limit (0.19 µM) and fast response (10 s). EuUHIPA-30 is recyclable and can detect DIC in chicken and eggs with good recoveries. Moreover, a smartphone-integrated paper-based sensor enables the instrument-free, rapid, visual, and intelligent detection of DIC in chickens and eggs. This work provides a promising candidate for practical fluorescent DIC sensing in animal-derived food to promote food safety.


Assuntos
Galinhas , Ovos , Európio , Contaminação de Alimentos , Estruturas Metalorgânicas , Nitrilas , Triazinas , Triazinas/análise , Animais , Ovos/análise , Nitrilas/química , Nitrilas/análise , Contaminação de Alimentos/análise , Estruturas Metalorgânicas/química , Európio/química , Limite de Detecção , Espectrometria de Fluorescência/métodos , Coccidiostáticos/análise
9.
Int J Biol Macromol ; 270(Pt 1): 132056, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38704070

RESUMO

Since the potential carcinogenic, toxic and non-degradable dyes trigger serious environmental contamination by improper treatment, developing novel adsorbents remains a major challenge. A novel high efficiency and biopolymer-based environmental-friendly adsorbent, chitosan­sodium tripolyphosphate-melamine sponge (CTS-STPP-MS) composite, was prepared for Orange II removing with chitosan as raw material, sodium tripolyphosphate as cross-linking agent. The composite was carefully characterized by SEM, EDS, FT-IR and XPS. The influence of crosslinking conditions, dosage, pH, initial concentration, contacting time and temperature on adsorption were tested through batch adsorption experiments. CTS-STPP-MS adsorption process was exothermic, spontaneous and agreed with Sips isotherm model accompanying the maximum adsorption capacity as 948 mg∙g-1 (pH = 3). Notably, the adsorption performance was outstanding for high concentration solutions, with a removal rate of 97 % in up to 2000 mg∙L-1 OII solution (100 mg sorbent dosage, 50 mL OII solution, pH = 3, 289.15 K). In addition, the adsorption efficiency yet remained 97.85 % after 5 repeated adsorption-desorption cycles. The driving force of adsorption was attributed to electrostatic attraction and hydrogen bonds which was proved by adsorption results coupled with XPS. Owing to the excellent properties of high-effective, environmental-friendly, easy to separate and regenerable, CTS-STPP-MS composite turned out to be a promising adsorbent in contamination treatment.


Assuntos
Compostos Azo , Quitosana , Triazinas , Poluentes Químicos da Água , Quitosana/química , Quitosana/análogos & derivados , Adsorção , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Triazinas/química , Compostos Azo/química , Compostos Azo/isolamento & purificação , Concentração de Íons de Hidrogênio , Purificação da Água/métodos , Benzenossulfonatos/química , Cinética , Polifosfatos/química , Ânions/química , Temperatura , Corantes/química , Corantes/isolamento & purificação
10.
Chemosphere ; 359: 142298, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38729438

RESUMO

Japanese radish (Raphanus sativus var. longipinnatus) plants grown under laboratory conditions were individually exposed to the same doses of atrazine (2-chloro-4-ethylamino-6-isopropylamino-1,3,5-triazine, ATR) or its main degradation products: either 2-amino-4-chloro-6-isopropylamino-1,3,5-triazine (DEA) or 2-amino-4-chloro-6-ethylamino-1,3,5-triazine (DIA) or desethyl-desisopropyl-atrazine (DEDIA) or 4-(ethylamino)-2-hydroxy-6-(isopropylamino)-1,3,5-triazine (HA), respectively. One week after treatment in plants exposed to ATR, DIA, and DEA, their concentrations were 7.8 µg/g, 9.7 µg/g, and 14.5 µg/g, respectively, while those treated with DEDIA and HA did not contain these compounds. These results were correlated with plant amino acid profile obtained by suspect screening analysis and metabolomic "fingerprint" based on non-target analysis, obtained by liquid chromatography coupled with QTRAP triple quadrupole mass spectrometer. In all cases, both ATR and its by-products were found to interfere with the plant's amino acid profile and modify its metabolic "fingerprint". Therefore, we proved that the non-target metabolomics approach is an effective tool for investigating the hidden effects of pesticides and their transformation products, which is particularly important as these compounds may reduce the quality of edible plants.


Assuntos
Atrazina , Herbicidas , Metabolômica , Raphanus , Atrazina/toxicidade , Raphanus/efeitos dos fármacos , Raphanus/metabolismo , Herbicidas/toxicidade , Triazinas/toxicidade
11.
Int J Biol Macromol ; 270(Pt 1): 132260, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38734338

RESUMO

The utilization of bioderived flame retardants in biodegradable poly (lactic acid) (PLA) has profound practical implications for extending the widespread application of PLA composites and protecting the environment. Nevertheless, there are still certain challenges that require prompt attention, especially the ineffectiveness of bio-based flame retardants and their deterioration of the mechanical properties of PLA. This work introduced triglycidyl isocyanurate (TGIC), which has multiple epoxy functions, into the self-assembly process of phytic acid (PA) and chitosan (CS). The epoxy-modified bioderived flame retardant PA@CS-TGIC (PCT) was well dispersed in the PLA matrix and had a strong interfacial adhesion, while also TGIC had a synergistic char-forming effect. By compounding epoxy-modified ammonium polyphosphate (MAPP), 3%PCT/MAPP-PLA composites may reach a LOI value of 28.8 % and UL-94 V-0 rating. Simultaneously, the melting droplets had been considerably reduced. Tensile strength of the 3%PCT/MAPP-PLA composites was 67.0 MPa, 10.8 % higher than that of pure PLA. This work paves a new avenue for the development of PLA composites with robust mechanical and flame retardant properties.


Assuntos
Retardadores de Chama , Poliésteres , Poliésteres/química , Resistência à Tração , Quitosana/química , Ácido Fítico/química , Triazinas/química
12.
Lung Cancer ; 192: 107820, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38763104

RESUMO

INTRODUCTION: Dysregulated MET is an established oncogenic driver in non-small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. METHODS: Patients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. RESULTS: The primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5-85.7) and 50.9 % (35.6-66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5-19.2) and 4.2 months (1.8-7.4). The overall response rate (95 % CI) was 25.0 % (7.3-52.4) and 16.7 % (5.6-34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). CONCLUSIONS: Capmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. TRIAL REGISTRATION: ClinicalTrials.gov NCT02323126.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Neoplasias Pulmonares , Nivolumabe , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Feminino , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptores ErbB/genética , Receptores ErbB/antagonistas & inibidores , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Adulto , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/metabolismo , Idoso de 80 Anos ou mais , Acrilamidas/uso terapêutico , Acrilamidas/administração & dosagem , Imidazóis , Triazinas
13.
ACS Appl Mater Interfaces ; 16(22): 29235-29247, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38769743

RESUMO

Expanding the functions and applications of DNA by integrating noncanonical bases and structures into biopolymers is a continuous scientific effort. An adenine-rich strand (A-strand) is introduced as functional scaffold revealing, in the presence of the low-molecular-weight cofactor cyanuric acid (CA, pKa 6.9), supramolecular hydrogel-forming efficacies demonstrating multiple pH-responsiveness. At pH 1.2, the A-strand transforms into a parallel A-motif duplex hydrogel cross-linked by AH+-H+A units due to the protonation of adenine (pKa 3.5). At pH 5.2, and in the presence of coadded CA, a helicene-like configuration is formed between adenine and protonated CA, generating a parallel A-CA triplex cross-linked hydrogel. At pH 8.0, the hydrogel undergoes transition into a liquid state by deprotonation of CA cofactor units and disassembly of A-CA triplex into its constituent components. Density functional theory calculations and molecular dynamics simulations, supporting the structural reconfigurations of A-strand in the presence of CA, are performed. The sequential pH-stimulated hydrogel states are rheometrically characterized. The hydrogel framework is loaded with fluorescein-labeled insulin, and the pH-stimulated release of insulin from the hydrogel across the pH barriers present in the gastrointestinal tract is demonstrated. The results provide principles for future application of the hydrogel for oral insulin administration for diabetes.


Assuntos
Adenina , DNA , Hidrogéis , Triazinas , Hidrogéis/química , Concentração de Íons de Hidrogênio , DNA/química , Adenina/química , Triazinas/química , Simulação de Dinâmica Molecular , Insulina/química
14.
J Agric Food Chem ; 72(23): 12946-12955, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38809794

RESUMO

Protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) is one of the most important targets for the discovery of green herbicides. In order to find novel PPO inhibitors with a higher herbicidal activity, a series of novel N-phenyltriazinone derivatives containing oxime ether and oxime ester groups were designed and synthesized based on the strategy of pharmacophore and scaffold hopping. Bioassay results revealed that some compounds showed herbicidal activities; especially, compound B16 exhibited broad-spectrum and excellent 100% herbicidal effects to Echinochloa crusgalli, Digitaria sanguinalis, Setaria faberii, Abutilon juncea, Amaranthus retroflexus, and Portulaca oleracea at a concentration of 37.5 g a.i./ha, which were comparable to trifludimoxazin. Nicotiana tabacum PPO (NtPPO) enzyme inhibitory assay indicated that B16 showed an excellent enzyme inhibitory activity with a value of 32.14 nM, which was similar to that of trifludimoxazin (31.33 nM). Meanwhile, compound B16 revealed more safety for crops (rice, maize, wheat, peanut, soybean, and cotton) than trifludimoxazin at a dose of 150 g a.i./ha. Moreover, molecular docking and molecular dynamics simulation further showed that B16 has a very strong and stable binding to NtPPO. It indicated that B16 can be used as a potential PPO inhibitor and herbicide candidate for application in the field.


Assuntos
Inibidores Enzimáticos , Herbicidas , Simulação de Acoplamento Molecular , Oximas , Proteínas de Plantas , Plantas Daninhas , Protoporfirinogênio Oxidase , Protoporfirinogênio Oxidase/antagonistas & inibidores , Protoporfirinogênio Oxidase/química , Protoporfirinogênio Oxidase/metabolismo , Herbicidas/farmacologia , Herbicidas/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Oximas/química , Oximas/farmacologia , Relação Estrutura-Atividade , Plantas Daninhas/efeitos dos fármacos , Plantas Daninhas/enzimologia , Proteínas de Plantas/química , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Triazinas/química , Triazinas/farmacologia , Ésteres/química , Ésteres/farmacologia , Estrutura Molecular , Éteres/química , Éteres/farmacologia , Descoberta de Drogas
15.
Invest New Drugs ; 42(3): 335-339, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38700578

RESUMO

MET exon 14 skipping alterations and MET amplifications are recognized as oncogenic and targetable genetic changes in cancer patients. The treatment of MET-selective tyrosine kinase inhibitors (TKIs) in this specific population has shown encouraging therapeutic results. However, a comprehensive understanding of the potential toxicities linked to these agents is still lacking. The present pharmacovigilance analysis was carried out using the FDA Adverse Event Reporting System database to assess notable adverse events associated with MET-selective TKIs. Gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and disturbances in metabolism and nutrition demonstrated a substantial prevalence and significance among the adverse event (AE) categories. Particularly notable were the occurrences of peripheral oedema, nausea, dysphagia, fatigue, and dyspnoea, which emerged as the foremost five reported AEs. The majority of these AEs were observed within the initial months of initiating treatment with MET-selective TKIs and persistently thereafter. Notably, our investigation unveiled a significant correlation between the usage of capmatinib and the incidence of hearing loss and difficulty in swallowing. Diligent monitoring and the implementation of supportive care strategies are essential in managing the toxicities associated with MET-selective TKIs, particularly those related to gastrointestinal disorders, respiratory toxicity, hepatotoxicity, and ototoxicity.


Assuntos
Farmacovigilância , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-met , Humanos , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Sistemas de Notificação de Reações Adversas a Medicamentos , Adulto , Neoplasias/tratamento farmacológico , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Idoso de 80 Anos ou mais , Triazinas/efeitos adversos , Imidazóis
16.
Mikrochim Acta ; 191(6): 335, 2024 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-38760484

RESUMO

The release of tire wear substances in the environment is raising concerns about potential impacts on aquatic ecosystems. The purpose of this study was to develop a quick and inexpensive screening test for the following tire wear substances: 6-phenylphenyldiamine quinone (6-PPD quinone), hexamethoxymethylmelamine (HMMM), 1-3-diphenylguanidine (1,3-DPG), and melamine. A dual strategy consisting of nanogold (nAu) signal intensity and the plasmonic ruler principle was used based on the spectral shift from the unaggregated free-form nAu from 525 nm to aggregated nAu at higher wavelengths. The shift in resonance corresponded to the relative sizes of the tire wear substances at the surface of nAu: 6-PPD (560 nm), HMMM (590 nm), 1,3-DPG (620 nm), and melamine (660 nm) in a concentration-dependent manner. When present in mixtures, a large indiscriminate band between 550 and 660 nm with a maximum corresponding to the mean intermolecular distance of 0.43 nm from the tested individual substances suggests that all compounds indiscriminately interacted at the surface of nAu. An internal calibration methodology was developed for mixtures and biological extracts from mussels and biofilms and revealed a proportional increase in absorbance at the corresponding resonance line for each test compound. Application of this simple and quick methodology revealed the increased presence of melamine and HMMM compounds in mussels and biofilms collected at urban sites (downstream city, road runoffs), respectively. The data also showed that treated municipal effluent decreased somewhat melamine levels in mussels.


Assuntos
Ouro , Nanopartículas Metálicas , Triazinas , Ouro/química , Nanopartículas Metálicas/química , Triazinas/análise , Triazinas/química , Ressonância de Plasmônio de Superfície/métodos , Poluentes Químicos da Água/análise
17.
Top Curr Chem (Cham) ; 382(2): 15, 2024 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-38703255

RESUMO

Aligned with the increasing importance of bioorthogonal chemistry has been an increasing demand for more potent, affordable, multifunctional, and programmable bioorthogonal reagents. More advanced synthetic chemistry techniques, including transition-metal-catalyzed cross-coupling reactions, C-H activation, photoinduced chemistry, and continuous flow chemistry, have been employed in synthesizing novel bioorthogonal reagents for universal purposes. We discuss herein recent developments regarding the synthesis of popular bioorthogonal reagents, with a focus on s-tetrazines, 1,2,4-triazines, trans-cyclooctenes, cyclooctynes, hetero-cycloheptynes, and -trans-cycloheptenes. This review aims to summarize and discuss the most representative synthetic approaches of these reagents and their derivatives that are useful in bioorthogonal chemistry. The preparation of these molecules and their derivatives utilizes both classical approaches as well as the latest organic chemistry methodologies.


Assuntos
Ciclo-Octanos , Triazinas , Triazinas/química , Triazinas/síntese química , Ciclo-Octanos/química , Ciclo-Octanos/síntese química , Alcinos/química , Alcinos/síntese química , Catálise , Indicadores e Reagentes/química , Estrutura Molecular
18.
Biol Pharm Bull ; 47(5): 967-977, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38763751

RESUMO

Ensitrelvir is a noncovalent inhibitor of the main protease (Mpro) of severe acute respiratory syndrome coronavirus 2. Acquisition of drug resistance in virus-derived proteins is a serious therapeutic concern, and drug resistance occurs due to amino acid mutations. In this study, we computationally constructed 24 mutants, in which one residue around the active site was replaced with alanine and performed molecular dynamics simulations to the complex of Mpro and ensitrelvir to predict the residues involved in drug resistance. We evaluated the changes in the entire protein structure and ligand configuration in each of these mutants and estimated which residues were involved in ensitrelvir recognition. This method is called a virtual alanine scan. In nine mutants (S1A, T26A, H41A, M49A, L141A, H163A, E166A, V186A, and R188A), although the entire protein structure and catalytic dyad (cysteine (Cys)145 and histidine (His)41) were not significantly moved, the ensitrelvir configuration changed. Thus, it is considered that these mutants did not recognize ensitrelvir while maintaining Mpro enzymatic activities, and Ser1, Thr26, His41, Met49, Leu141, His163, Glu166, Val186, and Arg188 may be related to ensitrelvir resistance. The ligand shift noted in M49A was similar to that observed in M49I, which has been shown to be experimentally ensitrelvir resistant. These findings suggest that our research approach can predict mutations that incite drug resistance.


Assuntos
Alanina , Domínio Catalítico , Proteases 3C de Coronavírus , Farmacorresistência Viral , Simulação de Dinâmica Molecular , SARS-CoV-2 , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , SARS-CoV-2/efeitos dos fármacos , Alanina/genética , Farmacorresistência Viral/genética , Humanos , Mutação , Tratamento Farmacológico da COVID-19 , Inibidores de Proteases/farmacologia , Indazóis , Triazinas , Triazóis
19.
J Chromatogr A ; 1726: 464977, 2024 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-38735117

RESUMO

A magnetic molecularly imprinted polymer (MMIP) adsorbent incorporating amino-functionalized magnetite nanoparticles, nitrogen-doped graphene quantum dots and mesoporous carbon (MIP@MPC@N-GQDs@Fe3O4NH2) was fabricated to extract triazine herbicides from fruit juice. The embedded magnetite nanoparticles simplified the isolation of the adsorbent from the sample solution. The N-GQDs and MPC enhanced adsorption by affinity binding with triazines. The MIP layer provided highly specific recognition sites for the selective adsorption of three target triazines. The extracted triazines were determined by high-performance liquid chromatography (HPLC) coupled with diode-array detection (DAD). The developed method exhibited linearity from 1.5 to 100.0 µg L-1 with a detection limit of 0.5 µg L-1. Recoveries from spiked fruit juice samples were in the range of 80.1- 108.4 %, with a relative standard deviation of less than 6.0 %. The developed MMIP adsorbent demonstrated good selectivity, high extraction efficiency, ease of fabrication and use, and good stability.


Assuntos
Carbono , Sucos de Frutas e Vegetais , Herbicidas , Limite de Detecção , Polímeros Molecularmente Impressos , Pontos Quânticos , Triazinas , Pontos Quânticos/química , Triazinas/química , Triazinas/análise , Triazinas/isolamento & purificação , Herbicidas/análise , Herbicidas/isolamento & purificação , Herbicidas/química , Sucos de Frutas e Vegetais/análise , Adsorção , Polímeros Molecularmente Impressos/química , Carbono/química , Cromatografia Líquida de Alta Pressão/métodos , Nanopartículas de Magnetita/química , Microextração em Fase Sólida/métodos , Impressão Molecular/métodos , Porosidade , Grafite/química
20.
Influenza Other Respir Viruses ; 18(5): e13302, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38706384

RESUMO

BACKGROUND: The transmission of influenza virus in households, especially by children, is a major route of infection. Prior studies suggest that timely antiviral treatment of ill cases may reduce infection in household contacts. The aim of the study was to compare the effects of oseltamivir (OTV) and baloxavir marboxil (BXM) treatment of index cases on the secondary attack rate (SAR) of influenza within household. METHODS: A post hoc analysis was done in BLOCKSTONE trial-a placebo-controlled, double-blinded post-exposure prophylaxis of BXM. Data were derived from the laboratory-confirmed index cases' household contacts who received placebo in the trial and also from household members who did not participate in the trial but completed illness questionnaires. To assess the SAR of household members, multivariate analyses adjusted for factors including age, vaccination status, and household size were performed and compared between contacts of index cases treated with BXM or OTV. RESULTS: In total, 185 index cases (116 treated with BXM and 69 treated with OTV) and 410 household contacts (201 from trial, 209 by questionnaire) were included. The Poisson regression modeling showed that the SAR in household contacts of index cases treated with BXM and OTV was 10.8% and 18.5%, respectively; the adjusted relative reduction in SAR was 41.8% (95% confidence interval: 1.0%-65.7%, p = 0.0456) greater with BXM than OTV. Similar reductions were found in contacts from the trial and those included by questionnaire. CONCLUSION: BXM treatment of index cases appeared to result in a greater reduction in secondary household transmission than OTV treatment.


Assuntos
Antivirais , Dibenzotiepinas , Características da Família , Influenza Humana , Morfolinas , Oseltamivir , Profilaxia Pós-Exposição , Piridonas , Triazinas , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/prevenção & controle , Influenza Humana/transmissão , Piridonas/uso terapêutico , Antivirais/uso terapêutico , Triazinas/uso terapêutico , Dibenzotiepinas/uso terapêutico , Feminino , Masculino , Oseltamivir/uso terapêutico , Adulto , Adolescente , Criança , Pessoa de Meia-Idade , Adulto Jovem , Profilaxia Pós-Exposição/métodos , Pré-Escolar , Morfolinas/uso terapêutico , Tiepinas/uso terapêutico , Método Duplo-Cego , Lactente , Piridinas/uso terapêutico , Idoso , Oxazinas/uso terapêutico
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