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1.
Anal Chim Acta ; 1207: 339708, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35491047

RESUMO

Organophosphate (OP) compounds are widely used in agriculture, industry, and even terrorism. It is important to distinguish high-toxicity OP compounds from low-toxicity OP compounds in dealing with chemical accidents. However, there are very few portable and simple detection methods. Mesoporous silica gated switches may provide an effective solution. In this study, a gated switch based on mesoporous silica as an inorganic scaffold loaded with sulforhodamine B and capped with acetylcholinesterase (AChE) was prepared for specific detection of OP compounds. Carbamate derivatives (G1-G6) were designed and synthetized as grafting compounds in consideration of the binding ability with AChE. Through further modification and optimization, grafting compound G6 with phenylpyridine as the substituent showed the best capping capacity, and it achieved excellent blocking of mesoporous silica gated switches for loaded sulforhodamine B. In the presence of high-toxicity OP compounds, low-toxicity OP compounds, AChE substrates and reversible AChE inhibitors respectively, only high-toxicity OP compounds could make the gated switch release loaded sulforhodamine B. The limit of detection for paraoxon-ethyl was 10.6 µΜ. Furthermore, the preparation process of the gated switch is fast and simple, and the prepared gated switch has good stability and rapid distinguishing ability. The results of this paper provide a new idea for rapidly distinguishing high-toxicity OP compounds from low-toxicity OP compounds and other related compounds on the spot.


Assuntos
Acetilcolinesterase , Organofosfatos , Acetilcolinesterase/química , Carbamatos , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Organofosfatos/toxicidade , Dióxido de Silício/química
2.
Environ Health Perspect ; 130(5): 57002, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35503735

RESUMO

BACKGROUND: Abnormal placental development may result in adverse pregnancy outcomes and metabolic diseases in adulthood; however, it remains unknown whether and how xenobiotics affect human placentation. OBJECTIVES: This study aimed to screen and identify placentation-disrupting chemicals in commonly used organophosphate flame retardants (OPFRs) and, if identified, to investigate potential adverse effects on placentation in relation to adverse pregnancy outcomes and metabolic disorder in offspring in mice. METHODS: We devised a high-throughput immunofluorescence screening assay based on human trophoblast organoids and used it to screen OPFRs that inhibit the proliferation of organoids. One identified chemical was assessed for its effects on placentation by evaluating villous cytotrophoblasts, syncytiotrophoblasts, and extravillous trophoblasts using immunofluorescence and a mitochondrial stress test after 2 d of exposure. A 10-d exposure study was further performed to observe the dynamic effect of the OPFR on the structure of the organoids. RNA-sequencing and western blotting experiments were performed to explore the associated pathways, and a potential binding protein was identified by immunoprecipitation and in vitro kinase activity assays. Animal studies were performed to determine whether the findings in organoids could be replicated in mice and to observe adverse pregnancy outcomes. RESULTS: The proliferation of organoids exposed to three aryl-OPFRs was significantly lower than the proliferation of control organoids. Further analysis demonstrated that one such chemical, 2-ethylhexyl-diphenyl phosphate (EHDPP), disrupted placentation in organoids. Mechanistically, EHDPP interfered with insulin-like growth factor 1 receptor (IGF1R) to inhibit aerobic respiration. Mice exposed to EHDPP at a physiological human concentrations exhibited immature and mature placental disorders, which correlated with fetal growth restriction, implantation failure, stillbirth, and impaired glucose tolerance. CONCLUSIONS: The human trophoblast organoid model showed that the commonly used OPFRs disrupted placentation via IGF1R, indicating that its use may contribute to adverse pregnancy outcomes and metabolic disorders in offspring. https://doi.org/10.1289/EHP10273.


Assuntos
Retardadores de Chama , Adulto , Animais , Feminino , Retardadores de Chama/metabolismo , Retardadores de Chama/toxicidade , Humanos , Camundongos , Organoides , Organofosfatos/metabolismo , Organofosfatos/toxicidade , Placenta , Placentação , Gravidez , Resultado da Gravidez , Trofoblastos
3.
Int J Mol Sci ; 23(7)2022 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-35409358

RESUMO

Tris (2-ethylhexyl) phosphate (TEHP) is an organophosphate flame retardant (OPFRs) which is extensively used as a plasticizer and has been detected in human body fluids. Contemporarily, toxicological studies on TEHP in human cells are very limited and there are few studies on its genotoxicity and cell death mechanism in human liver cells (HepG2). Herein, we find that HepG2 cells exposed to TEHP (100, 200, 400 µM) for 72 h reduced cell survival to 19.68%, 49.83%, 58.91% and 29.08%, 47.7% and 57.90%, measured by MTT and NRU assays. TEHP did not induce cytotoxicity at lower concentrations (5, 10, 25, 50 µM) after 24 h and 48 h of exposure. Flow cytometric analysis of TEHP-treated cells elevated intracellular reactive oxygen species (ROS), nitric oxide (NO), Ca++ influx and esterase levels, leading to mitochondrial dysfunction (ΔΨm). DNA damage analysis by comet assay showed 4.67, 9.35, 13.78-fold greater OTM values in TEHP (100, 200, 400 µM)-treated cells. Cell cycle analysis exhibited 23.1%, 29.6%, and 50.8% of cells in SubG1 apoptotic phase after TEHP (100, 200 and 400 µM) treatment. Immunofluorescence data affirmed the activation of P53, caspase 3 and 9 proteins in TEHP-treated cells. In qPCR array of 84 genes, HepG2 cells treated with TEHP (100 µM, 72 h) upregulated 10 genes and downregulated 4 genes belonging to a human cancer pathway. Our novel data categorically indicate that TEHP is an oxidative stressor and carcinogenic entity, which exaggerates mitochondrial functions to induce cyto- and genotoxicity and cell death, implying its hepatotoxic features.


Assuntos
Fosfatos , Transcriptoma , Dano ao DNA , Humanos , Fígado , Organofosfatos/toxicidade , Compostos Organofosforados/toxicidade
4.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35443546

RESUMO

Organophosphorus compound poisoning is a widely common problem in a developing country like Indian and it is a major clinical and public health concern. There have been efforts to find novel tools / markers to assess the prognosis and the use of RDW has been proposed in the OPCs poisoning, where in RDW can be used as a predictor of outcomes in OPCs poisoning. There have been several attempts to find out whether RDW can infact be used as a predictor of outcomes, but almost all of these studies so far have been done on a retrospective study. Hence our objective was to evaluate the association of RDW with the outcome of Organophosphate poisoning Material: The study consisted of 115 patients who were admitted to JSS hospital critical care due to consumption of Organophosphorus compounds. Patients were assessed and Blood investigations like Complete hemogram and Serum Cholinesterase levels collected after Informed consent was taken from the kin of the patients. Detailed History about the circumstances of consumption and the type of poison was collected and on arrival vitals were recorded. Observation: The mean age of the patient's in our study was 36.73 years. Out of the total patients 80% were males and 20% were females. The patients were divided into 3 groups; 1)Discharged without acute complications; 2) Discharged but had complications 3) Death; with 52% patients in group 1 and 27% patients in group 2 and 20.9% were in group 3. The most common complication in the group 2 was respiratory failure. RDW as a predictor for outcomes in Organophosphate compounds has a Sensitivity of 87.5% and specificity of 51.65% with a diagnostic accuracy of 59.13%. But as an independent predictor of mortality it was not significant. Conclusion: RDW can be used as a predictor of outcomes in Organophosphate compound poisoning cases with as RDW was elevated in cases with complications and death and was found to be significant. But as an independent predictor for mortality, it was not significant.


Assuntos
Intoxicação por Organofosfatos , Adulto , Feminino , Hospitalização , Humanos , Masculino , Intoxicação por Organofosfatos/diagnóstico , Organofosfatos , Compostos Organofosforados , Estudos Retrospectivos
5.
J Assoc Physicians India ; 70(4): 11-12, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35443548

RESUMO

Organophosphate compounds (OPC) cause most selfpoisoning deaths in India due to their easy availability and lack of stringent laws. AIM: To evaluate the clinical profile and outcome of the patients presenting with OPC poisoning and to study the prognostic value of Peradeniya Organophosphorus Poisoning Scale (POPS) in predicting the clinical outcomes. MATERIAL: This was a prospective study involving 100 patients of OPC poisoning admitted to Tata Main Hospital from June 2018 to May 2020 based on the inclusion criteria. Demographic profile, clinical features, treatment details, and need for ventilatory support were noted. POPS was applied on admission, and the patients were followed up for the outcome in terms of morbidity and mortality. OBSERVATION: Of the 100 patients, most patients were between 20 and 29 years with male to female ratio being 1.2:1. Vomiting (94%), followed by excessive secretions (84%) were the most common symptoms. Overall mortality was 22%. On grading of severity as per the POP scale, 27% of the patients had mild poisoning, 37% patients had moderate, whereas 36% had severe poisoning. Only 11.11% of the patients with POPS 0-3 required ventilator support, whereas 16.2% of the patients with POPS 4-7, and 100% of patients with POPS 8-11 required ventilator assistance (P < 0.0001). Similarly, the total dose of atropine required (P < 0.0001), length of intensive care unit (ICU) stay, complications, and mortality (P < 0.0001) were significantly associated with higher POPS. CONCLUSION: POPS at admission, correlated well with the need for ventilator support, the total dose of atropine required, length of stay in the ICU, complications, and mortality. It can thus be used for prognostication and risk stratification of patients with OPC poisoning.


Assuntos
Intoxicação por Organofosfatos , Atropina/uso terapêutico , Feminino , Humanos , Masculino , Intoxicação por Organofosfatos/diagnóstico , Intoxicação por Organofosfatos/terapia , Organofosfatos/uso terapêutico , Compostos Organofosforados/uso terapêutico , Prognóstico , Estudos Prospectivos , Centros de Atenção Terciária
6.
Molecules ; 27(7)2022 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-35408724

RESUMO

This study investigates the development of topically applied non-invasive chitosan-nanoparticles (CSNPs) for ocular delivery of tedizolid phosphate (TZP) for the treatment of MRSA-related ocular and orbital infections. An ionic-gelation method was used to prepare TZP-encapsulated CSNPs using tripolyphosphate-sodium (TPP) as cross-linker. Particle characterization was performed by the DLS technique (Zeta-Sizer), structural morphology was observed by SEM. The drug encapsulation and loading were determined by the indirect method. In-vitro release was conducted through dialysis bags in simulated tear fluid (pH 7) with 0.25% Tween-80. Physicochemical characterizations were performed for ocular suitability of CSNPS. An antimicrobial assay was conducted on different strains of Gram-positive bacteria. Eye-irritation from CSNPs was checked in rabbits. Transcorneal flux and apparent permeability of TZP from CSNPs was estimated through excised rabbit cornea. Ionic interaction between the anionic and cationic functional groups of TPP and CS, respectively, resulted in the formation of CSNPs at varying weight ratios of CS/TPP with magnetic stirring (700 rpm) for 4 h. The CS/TPP weight ratio of 3.11:1 with 10 mg of TZP resulted in optimal-sized CSNPs (129.13 nm) with high encapsulation (82%) and better drug loading (7%). Release profiles indicated 82% of the drug was released from the TZP aqueous suspension (TZP-AqS) within 1 h, while it took 12 h from F2 to release 78% of the drug. Sustained release of TZP from F2 was confirmed by applying different release kinetics models. Linearity in the profile (suggested by Higuchi's model) indicated the sustained release property CSNPs. F2 has shown significantly increased (p < 0.05) antibacterial activity against some Gram-positive strains including one MRSA strain (SA-6538). F2 exhibited a 2.4-fold increased transcorneal flux and apparent permeation of TZP as compared to TZP-AqS, indicating the better corneal retention. No sign or symptoms of discomfort in the rabbits' eyes were noted during the irritation test with F2 and blank CSNPs, indicating the non-irritant property of the TZP-CSNPs. Thus, the TZP-loaded CSNPs have strong potential for topical use in the treatment of ocular MRSA infections and related inflammatory conditions.


Assuntos
Quitosana , Nanopartículas , Animais , Quitosana/química , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Organofosfatos , Oxazóis , Tamanho da Partícula , Coelhos , Diálise Renal
7.
Anal Chim Acta ; 1206: 339792, 2022 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-35473871

RESUMO

Water-soluble non-conjugated polymer dots (PDs) have been synthesized using hyperbranched polyethyleneimine (PEI) and dihydroxybenzaldehyde (DHB) for the first time via the Schiff base reaction at room temperature. The yielded non-conjugated PDs of PEI-DHB could display the well-defined spheric structure and good water solubility. In contrast to the common PDs otherwise showing blue emission, the PEI-DHB PDs could give out strong green fluorescence in aqueous media. Especially, the fluorescence of the PEI-DHB PDs could be specifically quenched by MnO2 nanosheets through the inner filter effects and further restored by the thiocholine that could reduce MnO2 nanosheets into Mn2+. Herein, thiocholine could be produced in hydrolysis reaction of acetylthiocholine catalyzed by the acetylcholinesterase (AChE), of which the catalytic activity could be irreversibly inhibitted by the introduction of organophosphates. A highly selective fluorimetric method was thereby been developed for the detection of organophosphorus pesticides using dimethyl-dichloro-vinyl phosphate as a model. The linear concentrations ranges from 0.050 to 2.5 µM. Importantly, the non-conjugated PDs probes with strong green fluorescence and high water solubility may promise the extensive applications in the environmental, food, and clinical analysis fields.


Assuntos
Inseticidas , Praguicidas , Acetilcolinesterase/química , Inseticidas/análise , Compostos de Manganês , Organofosfatos/química , Compostos Organofosforados/análise , Óxidos , Praguicidas/análise , Polietilenoimina , Polímeros , Tiocolina/química , Água
8.
Water Sci Technol ; 85(8): 2423-2431, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35486465

RESUMO

Aggregation is a key process for determining the environmental behavior and impact of a nanoparticle (NP). Since organophosphate esters (OPEs), which are recognized as emerging contaminants, are distributed widely in the natural aquatic environment, they may contribute to interacting with NPs and ultimately influence their transport and fate. Here, we investigated two typical organophosphate esters OPEs on aggregation the Fe2O3 NP in aquatic environments. The results showed that both tri-ethylhexyl phosphate (TEHP) and tris (chloroisopropyl) phosphate (TCPP) improved the colloidal stability of Fe2O3 NP in artificial water and environmental matrices. TEHP exhibited an obvious effect than TCPP on the Zeta potential and aggregation rates of Fe2O3 NP in artificial water. In the presence of electrolyte, 10 mg/L TCPP and TEHP increased the critical coagulation concentration (CCC) by 3.6 times and 17.4 times, respectively. Compared with pore-water, the aggregation rates of Fe2O3 NP in river water were slightly higher than those in pore-water, which can be attributed to the higher DOC in pore-water. We suggested that the high hydrophobicity and molecular weight of OPEs were considered important factors against the aggregation of Fe2O3 NP in water. Greater surface charge and steric hindrance originating from TCPP and TEHP dominated the colloidal stability of Fe2O3 NP.


Assuntos
Nanopartículas , Poluentes Químicos da Água , Monitoramento Ambiental/métodos , Ésteres , Organofosfatos , Fosfatos , Água , Poluentes Químicos da Água/análise
9.
Int J Mol Sci ; 23(8)2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35457075

RESUMO

RT-qPCR is the gold standard and the most commonly used method for measuring gene expression. Selection of appropriate reference gene(s) for normalization is a crucial part of RT-qPCR experimental design, which allows accurate quantification and reliability of the results. Because there is no universal reference gene and even commonly used housekeeping genes' expression can vary under certain conditions, careful selection of an appropriate internal control must be performed for each cell type or tissue and experimental design. The aim of this study was to identify the most stable reference genes during osteogenic differentiation of the human osteosarcoma cell lines MG-63, HOS, and SaOS-2 using the geNorm, NormFinder, and BestKeeper statistical algorithms. Our results show that TBP, PPIA, YWHAZ, and EF1A1 are the most stably expressed genes, while ACTB, and 18S rRNA expressions are most variable. These data provide a basis for future RT-qPCR normalizations when studying gene expression during osteogenic differentiation, for example, in studies of osteoporosis and other bone diseases.


Assuntos
Genes Essenciais , Osteogênese , Proteínas 14-3-3/genética , Perfilação da Expressão Gênica/métodos , Humanos , Organofosfatos , Osteogênese/genética , Peptidilprolil Isomerase , Reação em Cadeia da Polimerase em Tempo Real/métodos , Padrões de Referência , Reprodutibilidade dos Testes , Proteína de Ligação a TATA-Box
10.
J Am Soc Mass Spectrom ; 33(5): 865-874, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35416666

RESUMO

Organophosphate esters are an emerging environmental concern since they spread persistently across all environmental compartments (air, soil, water, etc.). Measurements of semivolatile organic compounds are important but not without challenges due to their physicochemical properties. Selected ion flow tube-mass spectrometry (SIFT-MS) can be relevant for their analysis in air because it is a direct analytical method without separation that requires little preparation and no external calibration. SIFT-MS is based on the chemical reactivity of analytes with reactant ions. For volatile and semivolatile organic compound analysis in the gas phase, knowledge of ion-molecule reactions and kinetic parameters is essential for the utilization of this technology. In the present work, we focused on organophosphate esters, semivolatile compounds that are now ubiquitous in the environment. The ion-molecule reactions of eight precursor ions that are available in SIFT-MS (H3O+, NO+, O2•+, OH-, O•-, O2•-, NO2-, and NO3-) with six organophosphate esters were investigated. The modeling of ion-molecule reaction pathways by calculations supported and complemented the experimental work. Organophosphate esters reacted with six of the eight precursor ions with characteristic reaction mechanisms, such as protonation with hydronium precursor ions and association with NO+ ions, while nucleophilic substitution occurred with OH-, O•-, and O2•-. No reaction was observed with NO2- and NO3- ions. This work shows that the direct analysis of semivolatile organic compounds is feasible using SIFT-MS with both positive and negative ionization modes.


Assuntos
Ar , Dióxido de Nitrogênio , Ar/análise , Ésteres , Íons/química , Espectrometria de Massas/métodos , Dióxido de Nitrogênio/análise , Organofosfatos
11.
ACS Appl Mater Interfaces ; 14(17): 19241-19252, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35440137

RESUMO

A nanoreactor containing an evolved mutant of Saccharolobus solfataricus phosphotriesterase (L72C/Y97F/Y99F/W263V/I280T) as a catalytic bioscavenger was made for detoxification of organophosphates. This nanoreactor intended for treatment of organophosphate poisoning was studied against paraoxon (POX). Nanoreactors were low polydispersity polymersomes containing a high concentration of enzyme (20 µM). The polyethylene glycol-polypropylene sulfide membrane allowed for penetration of POX and exit of hydrolysis products. In vitro simulations under second order conditions showed that 1 µM enzyme inactivates 5 µM POX in less than 10 s. LD50-shift experiments of POX-challenged mice through intraperitoneal (i.p.) and subcutaneous (s.c.) injections showed that intravenous administration of nanoreactors (1.6 nmol enzyme) protected against 7 × LD50 i.p. in prophylaxis and 3.3 × LD50 i.p. in post-exposure treatment. For mice s.c.-challenged, LD50 shifts were more pronounced: 16.6 × LD50 in prophylaxis and 9.8 × LD50 in post-exposure treatment. Rotarod tests showed that transitory impaired neuromuscular functions of challenged mice were restored the day of experiments. No deterioration was observed in the following days and weeks. The high therapeutic index provided by prophylactic administration of enzyme nanoreactors suggests that no other drugs are needed for protection against acute POX toxicity. For post-exposure treatment, co-administration of classical drugs would certainly have beneficial effects against transient incapacitation.


Assuntos
Intoxicação por Organofosfatos , Hidrolases de Triester Fosfórico , Animais , Camundongos , Nanotecnologia , Intoxicação por Organofosfatos/tratamento farmacológico , Organofosfatos/toxicidade , Paraoxon
12.
Toxicology ; 472: 153181, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35439576

RESUMO

Organophosphates (OPs) are commonly used pesticides worldwide. Humans are exposed to OPs via different routes viz., the respiratory tract, gastrointestinal tract, and dermal integuments. OPs induce neuropathy by either phosphorylating acetyl cholinesterase or neuropathy target esterase, or by binding specifically to nicotinic or muscarinic receptors of nervous system. Other than neurobehavioral effects in humans, OPs cause cholinergic crisis, intermediate syndrome, OP-induced delayed neuropathy, and Chronic organophosphate-induced neuropsychiatric disorders in time and dosage dependent manner. Biomonitoring of OP markers from body fluids minimizes or measures the severity of the impact, allowing for timely control of the exposure. The standard treatments for OPs poisoning which avoid secondary organ damage are atropine administration, acetylcholine esterase restoration therapy with oximes, and general intensive care. This review summarizes the toxic manifestation data available on humans and discusses potential therapeutic modalities, with the aim to highlight the importance of increasing awareness about its potential risk and reevaluation of exposure level.


Assuntos
Inseticidas , Síndromes Neurotóxicas , Intoxicação por Organofosfatos , Praguicidas , Acetilcolinesterase , Humanos , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Intoxicação por Organofosfatos/tratamento farmacológico , Organofosfatos/toxicidade , Compostos Organofosforados , Praguicidas/toxicidade
13.
Toxicology ; 472: 153189, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35452779

RESUMO

Diazinon is an organophosphate pesticide that has a history of wide use. Developmental exposures to organophosphates lead to neurobehavioral changes that emerge early in life and can persist into adulthood. However, preclinical studies have generally evaluated changes through young adulthood, whereas the persistence or progression of deficits into middle age remain poorly understood. The current study evaluated the effects of maternal diazinon exposure on behavior and neurochemistry in middle age, at 1 year postpartum, comparing the results to our previous studies of outcomes at adolescence and in young adulthood (4 months of age) (Hawkey 2020). Female rats received 0, 0.5 or 1.0 mg/kg/day of diazinon via osmotic minipump throughout gestation and into the postpartum period. The offspring were tested on a battery of locomotor, affective, and cognitive tests at young adulthood and during middle age. Some of the neurobehavioral consequences of developmental DZN seen during adolescence and young adulthood faded with continued aging, whereas other neurobehavioral effects emerged with aging. At middle age, the rats showed few locomotor effects, in contrast to the locomotor hyperactivity that had been observed in adolescence. Notably, though, DZN exposure during development impaired reference memory performance in middle-aged males, an effect that had not been seen in the younger animals. Likewise, middle-aged females exposed to DZN showed deficient attentional accuracy, an effect not seen in young adults. Across adulthood, the continued potential for behavioral defects was associated with altered dopaminergic function, characterized by enhanced dopamine utilization that was regionally-selective (striatum but not frontal/parietal cortex). This study shows that the neurobehavioral impairments from maternal low dose exposure to diazinon not only persist, but may continue to evolve as animals enter middle age.


Assuntos
Diazinon , Inseticidas , Animais , Comportamento Animal , Diazinon/toxicidade , Feminino , Masculino , Organofosfatos/farmacologia , Compostos Organofosforados/farmacologia , Ratos
14.
Cancer Lett ; 537: 215591, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35398530

RESUMO

Addition of nab-paclitaxel to gemcitabine offers a survival benefit of only 6 weeks over gemcitabine alone at a cost of increased toxicity in PDAC. The goal of the present study is to evaluate the efficacy of Minnelide, a water-soluble prodrug of triptolide, in combination with the standard of care regimen for chemotherapy with the added advantage of reducing the doses of these drugs to minimize toxicity. Pancreatic cancer cell lines were implanted subcutaneously or orthotopically in athymic nude or C57BL/6J mice. Subsequently, animals were randomized and received saline or minnelide or full dose chemotherapy or low dose chemotherapy or minnelide in combination with low dose chemotherapy. Our results show that a combination of low doses of Minnelide with Gemcitabine + nab-paclitaxel significantly inhibited tumor progression and increased the survival of tumor-bearing mice in comparison with conventional chemotherapy alone. Moreover, combination therapy significantly reduced cancer-related morbidity by decreasing ascites and metastasis and effectively targeted both cancer and the associated stroma. In vitro studies with a combination of low doses of triptolide and paclitaxel significantly decreased the cell viability, increased apoptosis and led to significantly increased M-phase cell cycle arrest in various pancreatic cancer cell lines as compared to either drug alone. Our results show that Minnelide synergizes with conventional chemotherapy leading to a significant reduction in the doses of these toxic drugs, all the while achieving better efficacy in the treatment of PDAC. This combination effectively targeted both the cancer and the associated stromal components of pancreatic cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Pancreáticas , Albuminas , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Diterpenos , Compostos de Epóxi , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Organofosfatos , Paclitaxel , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Fenantrenos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Adv Exp Med Biol ; 1366: 45-64, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35412134

RESUMO

Gp120 is a critical viral proteins required for HIV-1 entry and infection. It facilitates HIV-1 binding to target cells, human-to-human transmission, relocation of virus from mucosa to lymph nodes, cell-cell infection and syncytium formation, and the bystander effect that kills uninfected CD4+ T-cells and other human cells. Molecules that bind to gp120 can inhibit its function by stabilizing conformations of the protein, leading to the inability to infect cells, and resulting in non-permissive. Small molecule-mediated stabilization of certain conformations of gp120 may also enhance recognition of HIV-1 infected cells by neutralizing antibodies and make the virus more susceptible to effector functions such as ADCC, which could potentially be part of future cure regimens. Additionally, HIV attachment inhibitors can complex with free gp120 and potentially repress both cytopathic effects from membrane-bound or soluble gp120. Fostemsavir (RukobiaTM), a phosphate prodrug of an HIV-1 attachment inhibitor that was recently approved for use in highly treatment experienced (HTE) patients with multidrug resistant HIV-1 is a first-in-class drug with a favorable safety profile that provides an additional treatment option for treatment in this population of patients with a high medical need.


Assuntos
Inibidores da Fusão de HIV , Infecções por HIV , HIV-1 , Anticorpos Neutralizantes , Antígenos CD4/metabolismo , Linfócitos T CD4-Positivos , Anticorpos Anti-HIV , Proteína gp120 do Envelope de HIV , Inibidores da Fusão de HIV/farmacologia , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Organofosfatos/uso terapêutico , Piperazinas/uso terapêutico
16.
Ecotoxicol Environ Saf ; 237: 113562, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35487175

RESUMO

In this study we have established a monitoring scheme to determine the presence and distribution of widely used pharmaceuticals, pesticides, organophosphate esters (OPEs) and perfluoroalkyl substances (PFAS) in water bodies from Important Bird and Biodiversity Areas (IBAs) from Spain. The monitoring scheme included the georeferenced sampling of rocky mountain, Atlantic forest, riparian forest, Mediterranean forest, agricultural, inland aquatic and coastal aquatic IBAs, with the aim to evaluate the impact of widely used chemicals in those aquatic resources. Water samples were extracted using a generic solid-phase extraction protocol and analyzed by 3 analytical methods based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Quality parameters such as compound recovery, intra and inter-day variation, linearity and limits of detection were calculated in order to validate the methods. In addition, the ionization conditions and the optimization of the most appropriate transitions permitted unequivocal identification. Once the sampling and analytical procedure was set-up, 59 target compounds were monitored in 63 samples. Pharmaceutical, followed by pesticides, OPEs and PFAS were widespread along all IBAs studied at concentrations from 0.5 to 41083 ng/L. Overall, this study highlights the need to monitor the presence of contaminants in areas of high ecological interest to contribute to pollution control and mitigation towards protection of biodiversity.


Assuntos
Fluorcarbonetos , Praguicidas , Poluentes Químicos da Água , Poluentes da Água , Animais , Biodiversidade , Aves , Cromatografia Líquida/métodos , Fluorcarbonetos/análise , Organofosfatos , Praguicidas/análise , Extração em Fase Sólida , Espectrometria de Massas em Tandem/métodos , Água , Poluentes da Água/análise , Poluentes Químicos da Água/análise
17.
Genes (Basel) ; 13(4)2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35456439

RESUMO

The simple and straightforward recognition of Triticum species is not an easy task due to their complex genetic origins. To provide a recommendation, we have compared the performance of different PCR-based methods relying on the discrimination ability of the Q- and γ-gliadin (GAG56D) genes, as well as TBP (Tubulin-Based Polymorphism), a method based on the multiple amplification of genes of the ß-tubulin family. Among these approaches, the PCR-RFLP (Restriction Fragment Length Polymorphism) assay based on a single-nucleotide polymorphism (SNP) present in the Q gene is the only one capable of fully discerning hexaploid spelt and common wheat species, while both γ-gliadin and TBP fail with similar error frequencies. The Q-locus assay results in the attainment of either a single fragment or a doublet, depending on the presence of a suitable restriction site, which is affected by the mutation. This dual pattern of resolution limits both the diagnostic effectiveness, when additional Triticum species are assayed and compared to each other, and its usefulness, when commercially available flours are analyzed. These limitations are overtaken by flanking the Q-locus assay with the TBP analysis. In this way, almost all of the Triticum species can be accurately identified.


Assuntos
Gliadina , Triticum , Farinha/análise , Gliadina/genética , Organofosfatos , Triticum/genética , Tubulina (Proteína)/genética
19.
PLoS One ; 17(4): e0267229, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35436317

RESUMO

BACKGROUND: Indoor residual spraying (IRS) using a capsule suspension formulation of the organophosphate insecticide, pirimiphos-methyl, has provided substantial malaria control in many communities in Africa. However, only one brand of this product has been recommended by the World Health Organisation for IRS. To help increase the diversity of the portfolio of IRS insecticides and offer suitable options to procurers and malaria vector control programmes, additional product brands of this highly effective and long-lasting insecticide formulation for IRS will be needed. METHODS: We evaluated the efficacy of Pirikool® 300CS, a new capsule suspension formulation of pirimiphos-methyl developed by Tianjin Yorkool, International Trading, Co., Ltd in standard WHO laboratory bioassays and experimental hut studies. The efficacy of the insecticide applied at 1000mg/m2 was assessed in laboratory bioassays for 6 months on cement, plywood and mud block substrates and for 12 months in cement and mud-walled experimental huts against wild free-flying pyrethroid-resistant Anopheles gambiae sensu lato in Covè, Benin. Actellic® 300CS, a WHO-recommended capsule suspension formulation of pirimiphos-methyl was also tested. WHO cylinder tests were performed to determine the frequency of insecticide resistance in the wild vector population during the hut trial. RESULTS: The vector population at the hut station was resistant to pyrethroids but susceptible to pirimiphos-methyl. Overall mortality rates of wild free-flying pyrethroid-resistant An. gambiae (s.l.) entering Pirikool®300CS treated experimental huts during the 12-month trial were 86.7% in cement-walled huts and 88% in mud-walled huts. Mortality of susceptible An. gambiae (Kisumu) and pyrethroid-resistant An. gambiae s.l. (Covè) mosquitoes in monthly wall cone bioassays on Pirikool® 300CS treated hut walls remained over 80% for 10-12 months. The laboratory bioassays corroborated the hut findings with Pirikool® 300CS on mud and wood block substrates but not on cement block substrates. CONCLUSION: Indoor residual spraying with Pirikool® 300CS induced high and prolonged mortality of wild pyrethroid-resistant malaria vectors for 10-12 months. Addition of Pirikool®300CS to the current portfolio of IRS insecticides will provide an extra choice of microencapsulated pirimiphos-methyl for IRS.


Assuntos
Anopheles , Inseticidas , Malária , Piretrinas , Animais , Benin , Resistência a Inseticidas , Inseticidas/farmacologia , Malária/prevenção & controle , Controle de Mosquitos , Mosquitos Vetores , Organofosfatos/farmacologia , Compostos Organotiofosforados , Piretrinas/farmacologia
20.
Environ Int ; 163: 107209, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35358787

RESUMO

Alkyl organophosphate flame retardants (OPFRs), tri-n-butyl phosphate (TnBP) and tris(2-butoxyethyl) phosphate (TBOEP), are ubiquitously detected in indoor and outdoor environments and their inhalation may result in lung damage. This study examined pulmonary toxicity after exposure to TnBP or TBOEP and investigated aggravation of inflammation and immunoreaction by TnBP in an ovalbumin (OVA)-induced mice model. Transcriptomics were used to further reveal the underlying mechanism. Exposure to TnBP or TBOEP resulted in pathological damage, including edema and thickened alveolar septum. In comparison with the control, enhanced levels of superoxide dismutase (SOD) (p < 0.01 in TnBP (High) group and p < 0.05 in TBOEP (High) group), glutathione peroxidase (GSH-px) (p < 0.05), malondialdehyde (MDA) (p < 0.01), and cytokines under a dose-dependent relationship were noted, and the expression of the Fkbp5/Nos3/MAPK/NF-кB signaling pathway (p < 0.01) was upregulated in the TnBP and TBOEP groups. Moreover, the combined exposure of TnBP and OVA exacerbated the allergic inflammatory response, including airway hyperresponsiveness, leukocytosis, cellular exudation and infiltration, secretion of inflammatory mediators, and higher expression of IgE (p < 0.01). Transcriptomics results demonstrated that the PI3K/Akt/NF-кB signal pathway was involved in TnBP-aggravated asthmatic mice. Exposure to TnBP or TBOEP resulted in oxidative damage and leukocyte-induced lung injury. TnBP can further facilitate OVA-induced asthma through an inflammatory response. This study is the first to reveal the pulmonary toxicity and potential mechanism induced by OPFRs through an in-vivo model.


Assuntos
Asma , Retardadores de Chama , Pneumonia , Animais , Asma/induzido quimicamente , Retardadores de Chama/toxicidade , Camundongos , NF-kappa B , Organofosfatos/toxicidade , Ovalbumina , Fosfatidilinositol 3-Quinases , Transdução de Sinais
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