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1.
JAMA ; 331(13): 1099-1108, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563835

RESUMO

Importance: Left atrial appendage elimination may improve catheter ablation outcomes for atrial fibrillation. Objective: To assess the safety and effectiveness of percutaneous left atrial appendage ligation adjunctive to catheter pulmonary vein isolation for nonparoxysmal atrial fibrillation. Design, Setting, and Participants: This multicenter, prospective, open-label, randomized clinical trial evaluated the safety and effectiveness of percutaneous left atrial appendage ligation adjunctive to planned pulmonary vein isolation for nonparoxysmal atrial fibrillation present for less than 3 years. Eligible patients were randomized in a 2:1 ratio to undergo left atrial appendage ligation and pulmonary vein isolation or pulmonary vein isolation alone. Use of a 2:1 randomization ratio was intended to provide more device experience and safety data. Patients were enrolled from October 2015 to December 2019 at 53 US sites, with the final follow-up visit on April 21, 2021. Interventions: Left atrial appendage ligation plus pulmonary vein isolation compared with pulmonary vein isolation alone. Main Outcomes and Measures: A bayesian adaptive analysis was used for primary end points. Primary effectiveness was freedom from documented atrial arrythmias of greater than 30 seconds duration 12 months after undergoing pulmonary vein isolation. Rhythm was assessed by Holter monitoring at 6 and 12 months after pulmonary vein isolation, symptomatic event monitoring, or any electrocardiographic tracing obtained through 12 months after pulmonary vein isolation. Primary safety was a composite of predefined serious adverse events compared with a prespecified 10% performance goal 30 days after the procedure. Left atrial appendage closure was evaluated through 12 months after pulmonary vein isolation. Results: Overall, 404 patients were randomized to undergo left atrial appendage ligation plus pulmonary vein isolation and 206 were randomized to undergo pulmonary vein isolation alone. Primary effectiveness was 64.3% with left atrial appendage ligation and pulmonary vein isolation and 59.9% with pulmonary vein isolation only (difference, 4.3% [bayesian 95% credible interval, -4.2% to 13.2%]; posterior superiority probability, 0.835), which did not meet the statistical criterion to establish superiority (0.977). Primary safety was met, with a 30-day serious adverse event rate of 3.4% (bayesian 95% credible interval, 2.0% to 5.0%; posterior probability, 1.0) which was less than the prespecified threshold of 10%. At 12 months after pulmonary vein isolation, complete left atrial appendage closure (0 mm residual communication) was observed in 84% of patients and less than or equal to 5 mm residual communication was observed in 99% of patients. Conclusions and Relevance: Percutaneous left atrial appendage ligation adjunctive to pulmonary vein isolation did not meet prespecified efficacy criteria for freedom from atrial arrhythmias at 12 months compared with pulmonary vein isolation alone for patients with nonparoxysmal atrial fibrillation, but met prespecified safety criteria and demonstrated high rates of closure at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT02513797.


Assuntos
Apêndice Atrial , Fibrilação Atrial , Compostos Organotiofosforados , Veias Pulmonares , Humanos , Apêndice Atrial/cirurgia , Fibrilação Atrial/cirurgia , Teorema de Bayes , Estudos Prospectivos , Veias Pulmonares/cirurgia , Ablação por Cateter , Cateterismo
2.
Technol Cancer Res Treat ; 23: 15330338241241898, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38557213

RESUMO

Introduction: In this study, we sought to develop a thermoplastic patient-specific helmet bolus that could deliver a uniform therapeutic dose to the target and minimize the dose to the normal brain during whole-scalp treatment with a humanoid head phantom. Methods: The bolus material was a commercial thermoplastic used for patient immobilization, and the holes in the netting were filled with melted paraffin. We compared volumetric-modulated arc therapy treatment plans with and without the bolus for quantitative dose distribution analysis. We analyzed the dose distribution in the region of interest to compare dose differences between target and normal organs. For quantitative analysis of treatment dose, OSLD chips were attached at the vertex (VX), posterior occipital (PO), right (RT), and left temporal (LT) locations. Results: The average dose in the clinical target volume was 6553.8 cGy (99.3%) with bolus and 5874 cGy (89%) without bolus, differing by more than 10% from the prescribed dose (6600 cGy) to the scalp target. For the normal brain, it was 3747.8 cGy (56.8%) with bolus and 5484.6 cGy (83.1%) without bolus. These results show that while the dose to the treatment target decreased, the average dose to the normal brain, which is mostly inside the treatment target, increased by more than 25%. With the bolus, the OSLD measured dose was 102.5 ± 1.2% for VX and 101.5 ± 1.9%, 95.9 ± 1.9%, and 81.8 ± 2.1% for PO, RT, and LT, respectively. In addition, the average dose in the treatment plan was 102%, 101%, 93.6%, and 80.7% for VX, PO, RT, and LT. When no bolus was administered, 59.6 ± 2.4%, 112.6 ± 1.8%, 47.1 ± 1.6%, and 53.1 ± 2.3% were assessed as OSLD doses for VX, PO, RT, and LT, respectively. Conclusion: This study proposed a method to fabricate patient-specific boluses that are highly reproducible, accessible, and easy to fabricate for radiotherapy to the entire scalp and can effectively spare normal tissue while delivering sufficient surface dose.


Assuntos
Compostos Organotiofosforados , Radioterapia de Intensidade Modulada , Humanos , Radioterapia de Intensidade Modulada/métodos , Couro Cabeludo , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador/métodos , Estudos de Viabilidade , Dispositivos de Proteção da Cabeça , Órgãos em Risco/efeitos da radiação
3.
Hematol Oncol ; 42(2): e3266, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38444261

RESUMO

Diffuse Large B-Cell Lymphomas (DLCBL) and mucosa-associated lymphoid tissue (MALT) are the two most common primary gastric lymphomas (PGLs), but have strongly different features. DLBCL is more aggressive, is frequently diagnosed at an advanced stage and has a poorer prognosis. The aim of this retrospective study was to explore the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (2-[18 F]-FDG-PET/CT) and radiomics features (RFs) in predicting the final diagnosis of patients with PGLs. Ninety-one patients with newly diagnosed PGLs who underwent pre-treatment 2-[18 F]-FDG-PET/CT were included. PET images were qualitatively and semi-quantitatively analyzed by deriving maximum standardized uptake value body weight (SUVbw), maximum standardized uptake value lean body mass (SUVlbm), maximum standardized uptake value body surface area (SUVbsa), lesion to liver SUVmax ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume (gMTV) and total lesion glycolysis of gastric lesion (gTLG), total MTV (tMTV), TLG, and first-order RFs (histogram-related and shape related). Receiver-operating characteristic (ROC) curve analyses were performed to determine the differential diagnostic values of PET parameters. The final diagnosis was DLBCL in 54 (59%) cases and MALT in 37 cases (41%). PGLs showed FDG avidity in 83 cases (90%), 54/54 of DLBCL and 29/37 of MALT. All PET/CT metabolic features, such as stage of disease and tumor size, were significantly higher in DLBCL than MALT; while the presence of H. Pylori infection was more common in MALT. At univariate analysis, all PET/CT metrics were significantly higher in DLBCL than MALT lymphomas, while among RFs only Shape volume_vx and Shape sphericity showed a significant difference between the two groups. In conclusion we demonstrated that 2-[18 F]-FDG-PET/CT parameters can potentially discriminate between DLBCL and MALT lymphomas with high accuracy. Among first-order RFs, only Shape volume_vx and Shape sphericity helped in the differential diagnosis.


Assuntos
Linfoma de Zona Marginal Tipo Células B , Linfoma não Hodgkin , Compostos Organotiofosforados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Gástricas , Humanos , Fluordesoxiglucose F18 , Estudos Retrospectivos
4.
Food Chem ; 447: 138976, 2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-38492300

RESUMO

This study examines the feasibility of replacing SO2 in a New Zealand Sauvignon Blanc wine with a green tea extract. The treatments included the control with no preservatives (C), the addition of green tea extract at 0.1 and 0.2 g/L (T1 and T2), and an SO2 treatment at 50 mg/L (T3). Five monomeric phenolic compounds were detected in the green tea extract used for the experiment, and their concentrations ranged in the order (-)-epigallocatechin gallate > (-)-epigallocatechin > (-)-epicatechin > (-)-epicatechin gallate > gallic acid. At the studied addition rates, these green tea-derived phenolic compounds contributed to ∼70% of the antioxidant capacity (ABTS), ∼71% of the total phenolic index (TPI), and âˆ¼ 84% of tannin concentration (MCPT) of the extract dissolved in a model wine solution. Among wine treatments, T1 and T2 significantly increased the wine's colour absorbance at 420 nm, MCPT, gallic acid and total monomeric phenolic content. TPI and ABTS were significantly higher in wines with preservatives (i.e., T2 > T1 â‰… T3 > C, p < 0.05). These variations were observed both two weeks after the treatments and again after five months of wine aging. Additionally, an accelerated browning test and a quantitative sensory analysis of wine colour and mouthfeel attributes were performed after 5 months of wine aging. When exposed to excessive oxygen and high temperature (50 °C), T1 and T2 exhibited ∼29% and 24% higher browning capacity than the control, whereas T3 reduced the wine's browning capacity by ∼20%. Nonetheless, the results from sensory analysis did not show significant variations between the treatments. Thus, using green tea extract to replace SO2 at wine bottling appears to be a viable option, without inducing a negative impact on the perceptible colour and mouthfeel attributes of Sauvignon Blanc wine.


Assuntos
Antioxidantes , Benzotiazóis , Compostos Organotiofosforados , Ácidos Sulfônicos , Vinho , Antioxidantes/análise , Vinho/análise , Dióxido de Enxofre/análise , Fermentação , Cor , Chá , Ácido Gálico/análise , Fenóis/análise , Extratos Vegetais/análise
5.
Biomolecules ; 14(3)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38540678

RESUMO

The present study aimed to investigate the effect of a H2S donor, GYY 4137, on human pulmonary arteries and whether low-frequency ultrasound (20 kHz, 4 W/cm2) inhibits GYY 4137 contractions. Functional studies were conducted on human and rat pulmonary arteries mounted on microvascular myographs. We placed an ultrasonic gadget in the tissue organ bath to insonate the arteries with low-frequency ultrasound. To measure the effect of the low-frequency ultrasound on the entrance of extracellular Ca2+, the preparations were placed in a Ca2+-free solution, and the thromboxane agonist, U46619, and extracellular calcium were added in the presence of insonation. In isolated human pulmonary arteries, GYY 4137 induced contractions, which were most pronounced in the arteries contracted with the thromboxane analogue, U46619. The transient GYY4137 contractions were reversed by low-frequency ultrasound, a blocker of KV7 channels, XE-991 (10 µM), and glibenclamide (1 µM), a blocker of ATP-sensitive channels. Low-frequency ultrasound also inhibited the contractions induced by the smooth muscle entrance of increasing extracellular calcium concentrations. The present findings show that GYY 4137 can cause a transient contraction of pulmonary arteries in human arteries. GYY 4137 alone does not cause significant vascular contraction in rat lung arteries, but it contracts rat lung arteries precontracted with U46619. The transient contractions induced by GYY 4137 can be inhibited by low-frequency ultrasound, probably by counteracting the influx of external Ca2+. The effect of low-frequency ultrasound counteracts contraction in pulmonary arteries; therefore, a possibility could be to develop a larger device allowing treatment of patients with pulmonary hypertension.


Assuntos
Morfolinas , Músculo Liso Vascular , Compostos Organotiofosforados , Artéria Pulmonar , Humanos , Ratos , Animais , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Cálcio/farmacologia , Tromboxanos/farmacologia
6.
BMC Genomics ; 25(1): 313, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38532318

RESUMO

BACKGROUND: Effective vector control is key to malaria prevention. However, this is now compromised by increased insecticide resistance due to continued reliance on insecticide-based control interventions. In Kenya, we have observed heterogenous resistance to pyrethroids and organophosphates in Anopheles arabiensis which is one of the most widespread malaria vectors in the country. We investigated the gene expression profiles of insecticide resistant An. arabiensis populations from Migori and Siaya counties in Western Kenya using RNA-Sequencing. Centers for Disease Control and Prevention (CDC) bottle assays were conducted using deltamethrin (DELTA), alphacypermethrin (ACYP) and pirimiphos-methyl (PMM) to determine the resistance status in both sites. RESULTS: Mosquitoes from Migori had average mortalities of 91%, 92% and 58% while those from Siaya had 85%, 86%, and 30% when exposed to DELTA, ACYP and PMM, respectively. RNA-Seq analysis was done on pools of mosquitoes which survived exposure ('resistant'), mosquitoes that were not exposed, and the insecticide-susceptible An. arabiensis Dongola strain. Gene expression profiles of resistant mosquitoes from both Migori and Siaya showed an overexpression mainly of salivary gland proteins belonging to both the short and long form D7 genes, and cuticular proteins (including CPR9, CPR10, CPR15, CPR16). Additionally, the overexpression of detoxification genes including cytochrome P450s (CYP9M1, CYP325H1, CYP4C27, CYP9L1 and CYP307A1), 2 carboxylesterases and a glutathione-S-transferase (GSTE4) were also shared between DELTA, ACYP, and PMM survivors, pointing to potential contribution to cross resistance to both pyrethroid and organophosphate insecticides. CONCLUSION: This study provides novel insights into the molecular basis of insecticide resistance in An. arabiensis in Western Kenya and suggests that salivary gland proteins and cuticular proteins are associated with resistance to multiple classes of insecticides.


Assuntos
Anopheles , Inseticidas , Malária , Compostos Organotiofosforados , Piretrinas , Animais , Inseticidas/farmacologia , Resistência a Inseticidas/genética , Anopheles/genética , Quênia , Mosquitos Vetores , Glutationa Transferase , Perfilação da Expressão Gênica , Proteínas e Peptídeos Salivares/genética , Glândulas Salivares
7.
Parasit Vectors ; 17(1): 66, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38365773

RESUMO

BACKGROUND: Efforts to evaluate the residual efficacy of new indoor residual spraying (IRS) formulations have identified limitations with the industry standard laboratory sprayer, the Potter Spray Tower (PT). Calibrating the PT can be time-consuming, and the dosing of surfaces may not be as accurate or uniform as previously assumed. METHODS: To address these limitations, the Micron Horizontal Track Sprayer with Spray Cabinet (TS) was developed to provide higher efficiency, ease of operation and deposition uniformity equal to or better than the PT. A series of studies were performed using a fluorescent tracer and three IRS formulations (Actellic® 300CS, K-Othrine WG250 and Suspend PolyZone) sprayed onto surfaces using either the PT or the TS. RESULTS: Deposition volumes could be accurately calibrated for both spray systems. However, the uniformity of spray deposits was higher for the TS compared to the PT. Less than 12% of the volume sprayed using the PT reaches the target surface, with the remaining 88% unaccounted for, presumably vented out of the fume hood or coating the internal surfaces of the tower. In contrast, the TS deposits most of the spray on the floor of the spray chamber, with the rest contained therein. The total sprayed surface area in one run of the TS is 1.2 m2, and the operational zone for spray target placement is 0.7 m2, meaning that 58% of the applied volume deposits onto the targets. The TS can treat multiple surfaces (18 standard 15 × 15 cm tiles) in a single application, whereas the PT treats one surface at a time and a maximum area of around 0.0225 m2. An assessment of the time taken to perform spraying, including the setup, calibration and cleaning, showed that the cost of application using the TS was around 25-35 × less per tile sprayed. Standard operating procedures (SOPs) for calibration and use of both the Potter Tower and Track Sprayer have been developed. CONCLUSIONS: Overall, the TS represents a significant improvement over the PT in terms of the efficiency and accuracy of IRS formulation applications onto test substrates and offers a useful additional tool for researchers and manufacturers wanting to screen new active ingredients or evaluate the efficacy of IRS or other sprayable formulations for insect control.


Assuntos
Anopheles , Inseticidas , Compostos Organotiofosforados , Animais , Controle de Insetos , Controle de Mosquitos/métodos
8.
Cancer Res Commun ; 4(3): 796-810, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38421899

RESUMO

Photodynamic therapy (PDT) is a tissue ablation technique able to selectively target tumor cells by activating the cytotoxicity of photosensitizer dyes with light. PDT is nonsurgical and tissue sparing, two advantages for treatments in anatomically complex disease sites such as the oral cavity. We have previously developed PORPHYSOME (PS) nanoparticles assembled from chlorin photosensitizer-containing building blocks (∼94,000 photosensitizers per particle) and capable of potent PDT. In this study, we demonstrate the selective uptake and curative tumor ablation of PS-enabled PDT in three preclinical models of oral cavity squamous cell carcinoma (OCSCC): biologically relevant subcutaneous Cal-33 (cell line) and MOC22 (syngeneic) mouse models, and an anatomically relevant orthotopic VX-2 rabbit model. Tumors selectively uptake PS (10 mg/kg, i.v.) with 6-to 40-fold greater concentration versus muscle 24 hours post-injection. Single PS nanoparticle-mediated PDT (PS-PDT) treatment (100 J/cm2, 100 mW/cm2) of Cal-33 tumors yielded significant apoptosis in 65.7% of tumor cells. Survival studies following PS-PDT treatments demonstrated 90% (36/40) overall response rate across all three tumor models. Complete tumor response was achieved in 65% of Cal-33 and 91% of MOC22 tumor mouse models 14 days after PS-PDT, and partial responses obtained in 25% and 9% of Cal-33 and MOC22 tumors, respectively. In buccal VX-2 rabbit tumors, combined surface and interstitial PS-PDT (200 J total) yielded complete responses in only 60% of rabbits 6 weeks after a single treatment whereas three repeated weekly treatments with PS-PDT (200 J/week) achieved complete ablation in 100% of tumors. PS-PDT treatments were well tolerated by animals with no treatment-associated toxicities and excellent cosmetic outcomes. SIGNIFICANCE: PS-PDT is a safe and repeatable treatment modality for OCSCC ablation. PS demonstrated tumor selective uptake and PS-PDT treatments achieved reproducible efficacy and effectiveness in multiple tumor models superior to other clinically tested photosensitizer drugs. Cosmetic and functional outcomes were excellent, and no clinically significant treatment-associated toxicities were detected. These results are enabling of window of opportunity trials for fluorescence-guided PS-PDT in patients with early-stage OCSCC scheduled for surgery.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Nanopartículas , Compostos Organotiofosforados , Fotoquimioterapia , Humanos , Animais , Coelhos , Camundongos , Fármacos Fotossensibilizantes/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Fotoquimioterapia/métodos , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Bucais/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Nanopartículas/uso terapêutico
9.
Ecotoxicol Environ Saf ; 273: 116126, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38387141

RESUMO

Nanopolystyrene (NP) and phoxim (PHO) are common environmental pollutants in aquatic systems. We evaluated the toxic effects of exposure to ambient concentrations of NP and/or PHO in the intestines of the Chinese mitten crab (Eriocheir sinensis). Our study showed that histopathological changes were observed in the intestines. Specifically, NP and/or PHO exposure increased intraepithelial lymphocytes. Furthermore, NP and/or PHO exposure induced oxidative stress, as evidenced by a significant decrease in superoxide dismutase activity (SOD), peroxidase activity (POD), and total antioxidant capacity (T-AOC). Pro-inflammatory gene expression and transcriptome analysis demonstrated that NP and/or PHO exposure induced the intestinal inflammatory response. Transcriptome results showed that NP and/or PHO exposure upregulated the NF-κB signaling pathway, which is considered a key pathway in the inflammatory response. Additionally, the expression of pro-inflammatory genes significantly increased after a single exposure to NP or PHO, but it exhibited a significant decrease after the co-exposure. The downregulation of these genes in the co-exposure group likely suggested that the co-exposure mitigated intestinal inflammation response in E. sinensis. Collectively, our findings mainly showed that NP and/or PHO exposure at ambient concentrations induces oxidative stress and inflammatory response in the intestines of E. sinensis.


Assuntos
Braquiúros , Compostos Organotiofosforados , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Intestinos , Inflamação/induzido quimicamente , Braquiúros/metabolismo
10.
Microbiol Res ; 282: 127638, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38422858

RESUMO

The plant-parasitic root-knot nematode Meloidogyne exigua causes significant damage and is an important threat in Coffea arabica plantations. The utilization of plant-beneficial microbes as biological control agents against sedentary endoparasitic nematodes has been a longstanding strategy. However, their application in field conditions to control root-knot nematodes and their interaction with the rhizospheric microbiota of coffee plants remain largely unexplored. This study aimed to investigate the effects of biological control agent-based bioproducts and a chemical nematicide, used in various combinations, on the control of root-knot nematodes and the profiling of the coffee plant rhizomicrobiome in a field trial. The commercially available biological products, including Trichoderma asperellum URM 5911 (Quality), Bacillus subtilis UFPEDA 764 (Rizos), Bacillus methylotrophicus UFPEDA 20 (Onix), and nematicide Cadusafos (Rugby), were applied to adult coffee plants. The population of second-stage juveniles (J2) and eggs, as well as plant yield, were evaluated over three consecutive years. However, no significant differences were observed between the control group and the groups treated with bioproducts and the nematicide. Furthermore, the diversity and community composition of bacteria, fungi, and eukaryotes in the rhizosphere soil of bioproduct-treated plants were evaluated. The dominant phyla identified in the 16 S, ITS2, and 18 S communities included Proteobacteria, Acidobacteria, Actinobacteria, Ascomycota, Mortierellomycota, and Cercozoa in both consecutive years. There were no significant differences detected in the Shannon diversity of 16 S, ITS2, and 18 S communities between the years of data. The application of a combination of T. asperellum, B. subtilis, and B. methylotrophicus, as well as the use of Cadusafos alone and in combination with T. asperellum, B. subtilis, and B. methylotrophicus, resulted in a significant reduction (26.08%, 39.13%, and 21.73%, respectively) in the relative abundance of Fusarium spp. Moreover, the relative abundance of Trichoderma spp. significantly increased by 500%, 200%, and 100% at the genus level, respectively, compared to the control treatment. By constructing a co-occurrence network, we discovered a complex network structure among the species in all the bioproduct-treated groups. However, our findings indicate that the introduction of exogenous beneficial microbes into field conditions was unable to modulate the existing microbiota significantly. These findings suggest that the applied bioproducts had no significant impact on the reshaping of the overall microbial diversity in the rhizosphere microbiome but rather recruited selected microrganisms and assured net return to the grower. The results underscore the intricate nature of the rhizosphere microbiome and suggest the necessity for alternate biocontrol strategies and a re-evaluation of agricultural practices to improve nematode control by aligning with the complex ecological interactions in the rhizosphere.


Assuntos
Coffea , Compostos Organotiofosforados , Tylenchoidea , Animais , Café , Solo/química , Microbiologia do Solo , Bactérias/genética , Antinematódeos , Coffea/microbiologia , Rizosfera , Agentes de Controle Biológico
11.
Mikrochim Acta ; 191(3): 164, 2024 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-38413405

RESUMO

A reliable, rapid, and inexpensive nano-sized chemosensor is presented for methamidophos (MET) - an insecticide. Poly(lactic acid) (PLA)-stabilized gold nanoparticles (AuNPs) were synthesized by a simple one-pot, two-phase chemical reduction method. The synthesized PLA-AuNPs were subsequently employed for selective, efficient, and quantitative detection of MET. MET is one of the highly toxic pesticides used for eradication of agricultural and urban insects. Upon the addition of MET, the wine-red color of PLA-AuNPs swiftly transformed into greyish-blue, further corroborated by a significant bathochromic and hyperchromic shift in the SPR band. The presence of other interfering insecticides, metal salts, and drugs did not have any pronounced effect on quantitative MET detection. The detection limit, the quantification limit, and linear dynamic range of MET utilizing PLA-AuNPs were  0.0027 µM, 0.005 µM, and 0.005-1000 µM, respectively. The PLA-AuNP-based assay renders an efficient, rapid, accurate, and selective quantification of MET in food, biological, and environmental samples. The proposed sensor provides an appropriate platform for fast and on-the-spot determination of MET without requiring a well-equipped lab setup.


Assuntos
Inseticidas , Nanopartículas Metálicas , Compostos Organotiofosforados , Ouro , Inseticidas/análise , Colorimetria/métodos , Poliésteres
12.
Toxicol Lett ; 393: 78-83, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38311194

RESUMO

Organ-on-a-chip technology is considered a next-generation platform in pharmacology and toxicology. Nevertheless, this novel technology still faces several challenges concerning the respective materials which are used for these microfluidic devices. Currently available organ-chips are most often based on polydimethylsiloxane (PDMS). However, this material has strong limitations regarding compound binding. The current study investigated options to reduce compound absorption of the highly toxic nerve agent VX (1000 µmol/L) in a commercially available organ-chip. In addition, surface effects on degradation products of VX were investigated. The alternative polymer cyclic olefin copolymers (CoC) showed significantly less compound absorption compared to PDMS. Furthermore, a coating of PDMS- and CoC-based chips was investigated. The biocompatible polymer polyethyleneimine (PEI) successfully modified PDMS and CoC surfaces and further reduced compound absorption. A previously examined VX concentration after 72 h of 141 ± 10 µmol/L VX could be increased to 442 ± 54 µmol/L. Finally, the respective concentrations of VX and degradation products accounted for > 90% of the initial concentration of 1000 µmol/L VX. The currently described surface modification might be a first step towards the optimization of organ-on-a-chip surfaces, facilitating a better comparability of different studies and results.


Assuntos
Agentes Neurotóxicos , Compostos Organotiofosforados , Agentes Neurotóxicos/toxicidade , Sistemas Microfisiológicos , Toxicocinética , Polímeros
13.
Bioorg Med Chem Lett ; 101: 129655, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38350529

RESUMO

The NaV1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.


Assuntos
Amidas , Neuralgia , Compostos Organotiofosforados , Humanos , Amidas/química , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Canal de Sódio Disparado por Voltagem NAV1.7 , Neuralgia/tratamento farmacológico , Neuralgia/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Piridonas/química , Piridonas/farmacologia
14.
PLoS Negl Trop Dis ; 18(2): e0011595, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38377131

RESUMO

Insecticide resistance is a serious threat to our ability to control mosquito vectors which transmit pathogens including malaria parasites and arboviruses. Understanding the underlying mechanisms is an essential first step in tackling the challenges presented by resistance. This study aimed to functionally characterise the carboxylesterase, CCEae3A, the elevated expression of which has been implicated in temephos resistance in Aedes aegypti and Aedes albopictus larvae. Using our GAL4/UAS expression system, already established in insecticide-sensitive Anopheles gambiae mosquitoes, we produced transgenic An. gambiae mosquitoes that express an Ae. aegypti CCEae3A ubiquitously. This new transgenic line permits examination of CCEae3A expression in a background in which there is not a clear orthologue in Vectorbase and allows comparison with existing An. gambiae GAL4-UAS lines. Insecticide resistance profiling of these transgenic An. gambiae larvae indicated significant increases in resistance ratio for three organophosphate insecticides, temephos (6), chloropyriphos (6.6) and fenthion (3.2) when compared to the parental strain. Cross resistance to adulticides from three major insecticide classes: organophosphates (malathion, fenitrothion and pirimiphos methyl), carbamates (bendiocarb and propoxur) and pyrethroid (alpha-cypermethrin) was also detected. Resistance to certain organophosphates and carbamates validates conclusions drawn from previous expression and phenotypic data. However, detection of resistance to pirimiphos methyl and alphacypermethrin has not previously been formally associated with CCEae3A, despite occurring in Ae. aegypti strains where this gene was upregulated. Our findings highlight the importance of characterising individual resistance mechanisms, thereby ensuring accurate information is used to guide future vector control strategies.


Assuntos
Aedes , Inseticidas , Compostos Organotiofosforados , Piretrinas , Animais , Aedes/genética , Carbamatos , Inseticidas/farmacologia , Organofosfatos/farmacologia , Temefós/farmacologia , Animais Geneticamente Modificados
15.
Arch Toxicol ; 98(3): 791-806, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38267661

RESUMO

We herein present for the first time the phosphylated (*) tetrapeptide (TP)-adduct GlyGluSer198*Ala generated from butyrylcholinesterase (BChE) with proteinase K excellently suited for the verification of exposure to toxic organophosphorus nerve agents (OPNA). Verification requires bioanalytical methods mandatory for toxicological and legal reasons. OPNA react with BChE by phosphonylation of the active site serine residue (Ser198) forming one of the major target protein adducts for verification. After its enzymatic cleavage with pepsin, the nonapeptide (NP) PheGlyGluSer*AlaGlyAlaAlaSer is typically produced as biomarker. Usually OPNA occur as racemic mixtures of phosphonic acid derivatives with the stereocenter at the phosphorus atom, e.g. (±)-VX. Both enantiomers react with BChE, but the adducted NP does not allow their chromatographic distinction. In contrast, the herein introduced TP-adducts appeared as two peaks when using a stationary reversed phase (1.8 µm) in micro-liquid chromatography-electrospray ionisation tandem-mass spectrometry (µLC-ESI MS/MS) analysis. These two peaks represent diastereomers of the (+)- and (-)-OPNA adducted to the peptide that comprises chiral L-amino acids exclusively. Concentration- and time-dependent effects of adduct formation with (±)-VX and its pure enantiomers (+)- and (-)-VX as well as with (±)-cyclosarin (GF) were investigated in detail characterising enantioselective adduct formation, stability, ageing and spontaneous reactivation. The method was also successfully applied to samples from a real case of pesticide poisoning as well as to samples of biomedical proficiency tests provided by the Organisation for the Prohibition of Chemical Weapons.


Assuntos
Substâncias para a Guerra Química , Agentes Neurotóxicos , Compostos Organotiofosforados , Butirilcolinesterase/metabolismo , Espectrometria de Massas em Tandem/métodos , Compostos Organotiofosforados/toxicidade , Compostos Organofosforados/toxicidade , Agentes Neurotóxicos/toxicidade , Substâncias para a Guerra Química/toxicidade , Substâncias para a Guerra Química/química
16.
J Clin Invest ; 134(5)2024 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-38227370

RESUMO

Two coding variants of apolipoprotein L1 (APOL1), called G1 and G2, explain much of the excess risk of kidney disease in African Americans. While various cytotoxic phenotypes have been reported in experimental models, the proximal mechanism by which G1 and G2 cause kidney disease is poorly understood. Here, we leveraged 3 experimental models and a recently reported small molecule blocker of APOL1 protein, VX-147, to identify the upstream mechanism of G1-induced cytotoxicity. In HEK293 cells, we demonstrated that G1-mediated Na+ import/K+ efflux triggered activation of GPCR/IP3-mediated calcium release from the ER, impaired mitochondrial ATP production, and impaired translation, which were all reversed by VX-147. In human urine-derived podocyte-like epithelial cells (HUPECs), we demonstrated that G1 caused cytotoxicity that was again reversible by VX-147. Finally, in podocytes isolated from APOL1 G1 transgenic mice, we showed that IFN-γ-mediated induction of G1 caused K+ efflux, activation of GPCR/IP3 signaling, and inhibition of translation, podocyte injury, and proteinuria, all reversed by VX-147. Together, these results establish APOL1-mediated Na+/K+ transport as the proximal driver of APOL1-mediated kidney disease.


Assuntos
Apolipoproteína L1 , Nefropatias , Compostos Organotiofosforados , Camundongos , Animais , Humanos , Apolipoproteína L1/genética , Células HEK293 , Variação Genética , Nefropatias/genética , Camundongos Transgênicos
17.
Cell Commun Signal ; 22(1): 33, 2024 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-38217003

RESUMO

BACKGROUND: Spinal cord ischemia‒reperfusion injury (SCIRI) can lead to paraplegia, which leads to permanent motor function loss. It is a disastrous complication of surgery and causes tremendous socioeconomic burden. However, effective treatments for SCIRI are still lacking. PANoptosis consists of three kinds of programmed cell death, pyroptosis, apoptosis, and necroptosis, and may contribute to ischemia‒reperfusion-induced neuron death. Previous studies have demonstrated that hydrogen sulfide (H2S) exerts a neuroprotective effect in many neurodegenerative diseases. However, whether H2S is anti-PANoptosis and neuroprotective in the progression of acute SCIRI remains unclear. Thus, in this study we aimed to explore the role of H2S in SCIRI and its underlying mechanisms. METHODS: Measurements of lower limb function, neuronal activity, microglia/macrophage function histopathological examinations, and biochemical levels were performed to examine the efficacy of H2S and to further demonstrate the mechanism and treatment of SCIRI. RESULTS: The results showed that GYY4137 (a slow-releasing H2S donor) treatment attenuated the loss of Nissl bodies after SCIRI and improved the BBB score. Additionally, the number of TUNEL-positive and cleaved caspase-3-positive cells was decreased, and the upregulation of expression of cleaved caspase-8, cleaved caspase-3, Bax, and Bad and downregulation of Bcl-2 expression were reversed after GYY4137 administration. Meanwhile, both the expression and activation of p-MLKL, p-RIP1, and p-RIP3, along with the number of PI-positive and RIP3-positive neurons, were decreased in GYY4137-treated rats. Furthermore, GYY4137 administration reduced the expression of NLRP3, cleaved caspase-1 and cleaved GSDMD, decreased the colocalization NeuN/NLRP3 and Iba1/interleukin-1ß-expressing cells, and inhibited proinflammatory factors and microglia/macrophage polarization. CONCLUSIONS: H2S ameliorated spinal cord neuron loss, prevented motor dysfunction after SCIRI, and exerted a neuroprotective effect via the inhibition of PANoptosis and overactivated microglia-mediated neuroinflammation in SCIRI.


Assuntos
Sulfeto de Hidrogênio , Morfolinas , Fármacos Neuroprotetores , Compostos Organotiofosforados , Traumatismo por Reperfusão , Ratos , Animais , Sulfeto de Hidrogênio/farmacologia , Sulfeto de Hidrogênio/uso terapêutico , Sulfeto de Hidrogênio/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Caspase 3/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Medula Espinal/metabolismo , Medula Espinal/patologia , Apoptose , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/metabolismo
18.
Anal Bioanal Chem ; 416(6): 1505-1515, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38267586

RESUMO

This study focuses on the detection of ethyl methyl phosphonic acid (EMPA), a metabolite of the banned organophosphorus nerve agent VX. We developed an electrochemical sensor utilizing the molecularly imprinted polymer (MIP) based on 4-aminobenzoic acid (4-ABA) and tetraethyl orthosilicate for the selective detection of EMPA in human plasma and urine samples. The 4-ABA@EMPA/MIP/GCE sensor was constructed by a thermal polymerization process on a glassy carbon electrode and sensor characterization was performed by cyclic voltammetry and electrochemical impedance spectroscopy. The 4-ABA@EMPA/MIP/GCE sensor demonstrated impressive linear ranges 1.0 × 10-10 M-2.5 × 10-9 M for the standard solution, 1.0 × 10-10 M-2.5 × 10-9 M for the urine sample, and 1.0 × 10-10 M-1 × 10-9 M of EMPA for the plasma sample with outstanding detection limits of 2.75 × 10-11 M (standard solution), 2.11 × 10-11 M (urine), and 2.36 × 10-11 M (plasma). The sensor exhibited excellent recovery percentages ranging from 99.86 to 101.30% in urine samples and 100.62 to 101.08% in plasma samples. These findings underscore the effectiveness of the 4-ABA@EMPA/MIP/GCE as a straightforward, highly sensitive, and selective interface capable of detecting the target analyte EMPA in human plasma and urine samples.


Assuntos
Antracenos , Impressão Molecular , Agentes Neurotóxicos , Organofosfonatos , Compostos Organotiofosforados , Humanos , Polímeros Molecularmente Impressos , Polímeros/química , Compostos Organofosforados , Técnicas Eletroquímicas/métodos , Impressão Molecular/métodos , Eletrodos , Limite de Detecção
19.
J Pharmacol Exp Ther ; 388(2): 386-398, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38050069

RESUMO

Nerve agents and organophosphates (OP) are neurotoxic chemicals that induce acute seizures, status epilepticus (SE), and mortality. Long-term neurologic and neurodegenerative effects manifest months to years after OP exposure. Current benzodiazepine anticonvulsants are ineffective in preventing such long-term neurobehavioral and neuropathological changes. New and effective anticonvulsants are needed for OP intoxication, especially for mitigating the long-term sequelae after acute exposure. We developed neurosteroids as novel anticonvulsants and neuroprotectants in OP exposure models. In this study, we evaluated the long-term efficacy of novel synthetic neurosteroids in preventing the development of chronic epilepsy and hyperexcitable ictal events in a rat OP model of SE. Rats were exposed to the OP nerve agent surrogate diisopropylfluorophosphate (DFP), and the experimental groups were treated with the synthetic neurosteroid valaxanolone (VX) or lysaxanolone (LX) 40 minutes post-exposure in conjunction with midazolam. Video-electroencephalography was monitored for two months to assess spontaneous recurrent seizures (SRS), epileptiform discharges, interictal spikes, and high-frequency oscillations (HFOs). Within 60 days of DFP exposure, rats developed chronic epilepsy characterized by frequent SRS, epileptiform discharges, and HFOs. LX treatment was associated with a dose-dependent reduction of epilepsy occurrence and overall seizure burden with a significant decrease in SRS and epileptiform discharges. It also significantly reduced the occurrence of epileptic biomarkers of HFOs and interictal spikes, indicating potential disease-modifying activity. Similarly, the neurosteroid analog VX also significantly attenuated SRS, discharges, HFOs, and ictal events. These results demonstrate the long-term protective effects of synthetic neurosteroids in the OP-exposed post-SE model, indicating their disease-modifying potential to prevent epilepsy and ictal abnormalities. SIGNIFICANCE STATEMENT: The effects of nerve agents and organophosphate (OP) exposure are persistent, and survivors suffer from a number of devastating, chronic neurological dysfunctions. Currently, there is no specific therapy for preventing this disastrous impact of OP exposure. We propose synthetic neurosteroids that activate tonic inhibition provide viable options for preventing the long-term neurological effects of OP intoxication. The results from this study reveal the disease-modifying potential of two novel synthetic neurosteroids in preventing epileptogenesis and chronic epileptic seizures after OP-induced SE.


Assuntos
Epilepsia , Agentes Neurotóxicos , Neuroesteroides , Intoxicação por Organofosfatos , Compostos Organotiofosforados , Estado Epiléptico , Ratos , Animais , Neuroesteroides/uso terapêutico , Anticonvulsivantes/efeitos adversos , Organofosfatos/efeitos adversos , Agentes Neurotóxicos/efeitos adversos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/prevenção & controle , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Epilepsia/tratamento farmacológico , Eletroencefalografia , Biomarcadores
20.
Arch Toxicol ; 98(1): 267-275, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38051368

RESUMO

Nerve agents are organophosphate chemical warfare agents that exert their toxic effects by irreversibly inhibiting acetylcholinesterase, affecting the breakdown of the neurotransmitter acetylcholine in the synaptic cleft. Due to the risk of exposure to dangerous nerve agents and for animal welfare reasons, in silico methods have been used to assess acute toxicity safely. The next-generation risk assessment (NGRA) is a new approach for predicting toxicological parameters that can meet modern requirements for toxicological research. The present study explains the acute toxicity of the examined V-series nerve agents (n = 9) using QSAR models. Toxicity Estimation Software Tool (ver. 4.2.1 and ver. 5.1.2), QSAR Toolbox (ver. 4.6), and ProTox-II browser application were used to predict the median lethal dose. The Simplified Molecular Input Line Entry Specification (SMILES) was the input data source. The results indicate that the most deadly V-agents were VX and VM, followed by structural VX analogues: RVX and CVX. The least toxic turned out to be V-sub x and Substance 100A. In silico methods for predicting various parameters are crucial for filling data gaps ahead of experimental research and preparing for the upcoming use of nerve agents.


Assuntos
Substâncias para a Guerra Química , Agentes Neurotóxicos , Compostos Organotiofosforados , Animais , Substâncias para a Guerra Química/toxicidade , Substâncias para a Guerra Química/química , Agentes Neurotóxicos/toxicidade , Agentes Neurotóxicos/química , Acetilcolinesterase/metabolismo , Compostos Organotiofosforados/toxicidade
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