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1.
PLoS Negl Trop Dis ; 14(3): e0007803, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32203503

RESUMEN

Non-typhoidal Salmonella enterica strains, including serovar Typhimurium (STm), are an emerging cause of invasive disease among children and the immunocompromised, especially in regions of sub-Saharan Africa. STm invades the intestinal mucosa through Peyer's patch tissues before disseminating systemically. While vaccine development efforts are ongoing, the emergence of multidrug resistant strains of STm affirms the need to seek alternative strategies to protect high-risk individuals from infection. In this report, we investigated the potential of an orally administered O5 serotype-specific IgA monoclonal antibody (mAb), called Sal4, to prevent infection of invasive Salmonella enterica serovar Typhimurium (STm) in mice. Sal4 IgA was delivered to mice prior to or concurrently with STm challenge. Infectivity was measured as bacterial burden in Peyer's patch tissues one day after challenge. Using this model, we defined the minimal amount of Sal4 IgA required to significantly reduce STm uptake into Peyer's patches. The relative efficacy of Sal4 in dimeric and secretory IgA (SIgA) forms was compared. To assess the role of isotype in oral passive immunization, we engineered a recombinant IgG1 mAb carrying the Sal4 variable regions and evaluated its ability to block invasion of STm into epithelial cells in vitro and Peyer's patch tissues. Our results demonstrate the potential of orally administered monoclonal IgA and SIgA, but not IgG, to passively immunize against invasive Salmonella. Nonetheless, the prophylactic window of IgA/SIgA in the mouse was on the order of minutes, underscoring the need to develop formulations to protect mAbs in the gastric environment and to permit sustained release in the small intestine.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Inmunoglobulina A/farmacología , Inmunoglobulina G/farmacología , Salmonella/efectos de los fármacos , Administración Oral , África , Animales , Modelos Animales de Enfermedad , Farmacorresistencia Bacteriana Múltiple/efectos de los fármacos , Femenino , Células HeLa , Humanos , Hibridomas , Inmunización Pasiva , Inmunoglobulina A Secretora , Inmunoglobulina G/genética , Ratones , Ratones Endogámicos BALB C , Ganglios Linfáticos Agregados , Salmonella typhimurium/efectos de los fármacos
3.
Mutat Res ; 849: 503137, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-32087853

RESUMEN

The International Workshop on Genotoxicity Testing (IWGT) meets every four years to obtain consensus on unresolved issues associated with genotoxicity testing. At the 2017 IWGT meeting in Tokyo, four sub-groups addressed issues associated with the Organization for Economic Cooperation and Development (OECD) Test Guideline TG471, which describes the use of bacterial reverse-mutation tests. The strains sub-group analyzed test data from >10,000 chemicals, tested additional chemicals, and concluded that some strains listed in TG471 are unnecessary because they detected fewer mutagens than other strains that the guideline describes as equivalent. Thus, they concluded that a smaller panel of strains would suffice to detect most mutagens. The laboratory proficiency sub-group recommended (a) establishing strain cell banks, (b) developing bacterial growth protocols that optimize assay sensitivity, and (c) testing "proficiency compounds" to gain assay experience and establish historical positive and control databases. The sub-group on criteria for assay evaluation recommended that laboratories (a) track positive and negative control data; (b) develop acceptability criteria for positive and negative controls; (c) optimize dose-spacing and the number of analyzable doses when there is evidence of toxicity; (d) use a combination of three criteria to evaluate results: a dose-related increase in revertants, a clear increase in revertants in at least one dose relative to the concurrent negative control, and at least one dose that produced an increase in revertants above control limits established by the laboratory from historical negative controls; and (e) establish experimental designs to resolve unclear results. The in silico sub-group summarized in silico utility as a tool in genotoxicity assessment but made no specific recommendations for TG471. Thus, the workgroup identified issues that could be addressed if TG471 is revised. The companion papers (a) provide evidence-based approaches, (b) recommend priorities, and (c) give examples of clearly defined terms to support revision of TG471.


Asunto(s)
Escherichia coli/efectos de los fármacos , Mutagénesis , Pruebas de Mutagenicidad/normas , Mutágenos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Animales , Bancos de Muestras Biológicas/organización & administración , Bases de Datos de Compuestos Químicos/provisión & distribución , Escherichia coli/genética , Guías como Asunto , Humanos , Cooperación Internacional , Mutágenos/clasificación , Salmonella typhimurium/genética , Tokio
4.
Int J Food Microbiol ; 321: 108560, 2020 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-32078866

RESUMEN

Foodborne illnesses affect the health of consumers worldwide, and thus searching for potential antimicrobial agents against foodborne pathogens is given an increased focus. This research evaluated the influence of sodium lactate (SL), encapsulated (e) and unencapsulated (u) polyphosphates (PP; sodium tripolyphosphate, STP; sodium acid pyrophosphate, SPP), and their combinations on Salmonella Typhimurium, Escherichia coli O157:H7 and Staphylococcus aureus growth in cooked ground beef during 30 day storage at 4 or 10 °C. pH, water activity (aw), oxidation-reduction potential (ORP) and S. Typhimurium, E. coli O157:H7 and S. aureus counts were determined. S. Typhimurium was not found in SPP-SL combination groups after 30 day storage at 4 °C (P <0.05). Lower S. Typhimurium levels were determined in only SL containing groups stored at 10 °C than group with only tested microorganism (MO, P < 0.05). Although there was no change in S. Typhimurium load in all SL incorporated groups during 10 °C storage, S. Typhimurium count increased in other groups (P < 0.05). E. coli O157:H7 in MO and STP groups showed an increase at 4 °C, whereas it decreased in SPP-SL combination groups (P < 0.05). A gradual increase in E. coli O157:H7 at 10 °C was determined in MO and only PP incorporated groups, whereas there was a decrease in STP-SL or SPP-SL combination groups (P < 0.05). E. coli O157:H7 count was stable in SL containing groups during 10 °C storage. A gradual decrease in S. aureus was determined in all treatments at 4 °C, whereas S. aureus count increased in MO and uSTP groups during 10 °C storage (P < 0.05). There was no change in S. aureus level in only eSTP or uSPP or ueSTP containing groups at 10 °C, meantime it decreased in other groups (P < 0.05). The lowest S. aureus load was achieved by uSPP-SL or eSPP-SL or ueSPP-SL combinations after 30 days at both storage temperatures (P < 0.05). In general, pH was higher in samples with STP than those with SPP and control (P < 0.05). The lowest aw was generally obtained in all SL containing groups at both storage temperatures (P < 0.05). Lower ORP was determined in all PP incorporated groups during storage at both temperatures compared to others (P < 0.05). ORP in all treatments generally increased (P < 0.05) during storage at both storage temperatures. This study showed that encapsulation is not a factor affecting antimicrobial efficiency of PP and using PP-SL combinations have synergistic effect on reducing the viability of S. Typhimurium, E. coli O157:H7 and S. aureus and their subsequent growth ability in cooked ground beef.


Asunto(s)
Escherichia coli O157/efectos de los fármacos , Polifosfatos/farmacología , Carne Roja/microbiología , Salmonella typhimurium/efectos de los fármacos , Lactato de Sodio/farmacología , Staphylococcus aureus/efectos de los fármacos , Animales , Cápsulas , Bovinos , Recuento de Colonia Microbiana , Sinergismo Farmacológico , Escherichia coli O157/crecimiento & desarrollo , Manipulación de Alimentos , Microbiología de Alimentos , Polifosfatos/química , Carne Roja/análisis , Salmonella typhimurium/crecimiento & desarrollo , Staphylococcus aureus/crecimiento & desarrollo , Temperatura
5.
Food Microbiol ; 87: 103387, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31948628

RESUMEN

We evaluated the bactericidal efficacy of the simultaneous application of ultraviolet-A (UV-A) irradiation and fumaric acid (FA) against Escherichia coli O157:H7, Salmonella enterica serovar Typhimurium, and Listeria monocytogenes in apple juice and as well as investigated the effects of this treatment on product quality. Further, we elucidated the mechanisms underlying their synergistic bactericidal action. Simultaneous UV-A light irradiation and 0.1% FA treatment for 30 min resulted in 6.65-, 6.27-, and 6.49-log CFU/ml reductions in E. coli O157:H7, S. Typhimurium, and L. monocytogenes, respectively, which involved 3.15, 2.21, and 3.43 log CFU reductions, respectively, and these were attributed to the synergistic action of the combined treatments. Mechanistic investigations suggested that the combined UVA-FA treatment resulted in significantly greater bacterial cell membrane damage and intracellular reactive oxygen species (ROS) generation. UVA-FA treatment for 30 min did not cause significant changes to the color, nonenzymatic browning index, pH, and total phenolic content of apple juice. These results suggest that combined UVA-FA treatment can be effectively used to control foodborne pathogens in apple juice without affecting its quality.


Asunto(s)
Antibacterianos/farmacología , Conservación de Alimentos/métodos , Jugos de Frutas y Vegetales/microbiología , Fumaratos/farmacología , Malus/microbiología , Escherichia coli O157/efectos de los fármacos , Escherichia coli O157/crecimiento & desarrollo , Escherichia coli O157/metabolismo , Escherichia coli O157/efectos de la radiación , Conservación de Alimentos/instrumentación , Jugos de Frutas y Vegetales/análisis , Listeria monocytogenes/efectos de los fármacos , Listeria monocytogenes/crecimiento & desarrollo , Listeria monocytogenes/metabolismo , Listeria monocytogenes/efectos de la radiación , Viabilidad Microbiana/efectos de los fármacos , Viabilidad Microbiana/efectos de la radiación , Especies Reactivas de Oxígeno/metabolismo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo , Salmonella typhimurium/metabolismo , Salmonella typhimurium/efectos de la radiación , Rayos Ultravioleta
6.
Food Microbiol ; 87: 103391, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-31948632

RESUMEN

In the present study, we investigated whether cold plasma activation affected the efficacy of aerosolized hydrogen peroxide against S. Typhimurium and L. innocua. Stem scars and smooth surfaces of grape tomatoes, surfaces of Granny Smith apples and Romaine lettuce (both midrib and upper leaves) and cantaloupe rinds were inoculated with two-strain cocktails of S. Typhimurium and 3-strain cocktails of L. innocua. The inoculated samples were treated with 7.8% aerosolized H2O2 with and without cold plasma for various times. For all fresh produce items and surfaces, cold plasma significantly (P < 0.05) improved the efficacy of aerosolized H2O2 against Salmonella and L. innocua. Without cold plasma activation, H2O2 aerosols only reduced populations of Salmonella by 1.54-3.17 log CFU/piece while H2O2 with cold plasma achieved 2.35-5.50 log CFU/piece reductions of Salmonella. L. innocua was more sensitive to the cold plasma-activated H2O2 than Salmonella. Cold plasma activated H2O2 aerosols reduced Listeria populations by more than 5 log CFU/piece on all types and surfaces of fresh produce except for the tomato stem scar area. Without cold plasma, the reductions by H2O2 were only 1.35-3.77 log CFU/piece. Overall, our results demonstrated that cold plasma activation significantly enhanced the efficacy of H2O2 mist against bacteria on fresh produce.


Asunto(s)
Cucumis melo/microbiología , Peróxido de Hidrógeno/farmacología , Lechuga/microbiología , Lycopersicon esculentum/efectos de los fármacos , Malus/microbiología , Gases em Plasma/farmacología , Salmonella typhimurium/efectos de los fármacos , Vitis/microbiología , Peróxido de Hidrógeno/química , Lycopersicon esculentum/crecimiento & desarrollo , Salmonella typhimurium/crecimiento & desarrollo
7.
Chem Biol Interact ; 315: 108870, 2020 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-31669216

RESUMEN

The toxic effects of poly(HEMA)-based polymeric nanoparticles must be analyzed before their biomedical applications as drug delivery systems. The aim of the study was to characterize and evaluate the toxicity for its biocompatibility of a newly synthesized l-glutamic acid-g-p(HEMA) polymeric nanoparticle The nanoparticle was synthesized with surfactant-free emulsion polymerization and grafting techniques. Grafting efficiency was estimated at 58%. The nanoparticle shape was verified as nearly spherical by scanning electron microscopy. Atomic force microscopy images showed a rough surface topography. The nanoparticle had an average size of ~194.6 nm on zeta analysis, and the zeta potential value was -18 mV. Fourier transformed infrared spectroscopy revealed spectra from 750 to 4000 cm-1 and characteristic peaks of stretching bands. The swelling ratio was 46%. With 24-h exposure, p(HEMA) and l-glutamic acid-g-p(HEMA) did not have cytotoxic effects on a human bronchial epithelial cell line (16HBE) and human monocyte cell line by water-soluble tetrazolium salt 1 (WST-1) assay and lactate dehydrogenase assay (LDH). It did not show genotoxic potential by comet assay and did not have mutagenic effects on Salmonella typhimurium TA98, TA100, TA1535 and TA1537 strains by Ames test. The nanoparticle at 160 µg/ml showed 2% hemolytic activity on erythrocytes. On cell migration assay, the percentage closure difference between exposed and control cells was estimated at 21%. We found no irritation effect on Hen's egg test-chorioallantoic membrane test. We determined that the polymeric nanoparticle l-glutamic acid-g-p(HEMA) was biocompatible and has potential for use in a drug delivery system.


Asunto(s)
Metacrilatos/química , Metacrilatos/toxicidad , Nanopartículas/química , Nanopartículas/toxicidad , Polímeros/química , Polímeros/toxicidad , Animales , Materiales Biocompatibles/química , Materiales Biocompatibles/toxicidad , Línea Celular , Pollos , Sistemas de Liberación de Medicamentos/métodos , Emulsiones/química , Emulsiones/farmacología , Emulsiones/toxicidad , Eritrocitos/efectos de los fármacos , Humanos , Monocitos/efectos de los fármacos , Tamaño de la Partícula , Conejos , Salmonella typhimurium/efectos de los fármacos , Propiedades de Superficie/efectos de los fármacos , Tensoactivos/química
8.
Chemosphere ; 239: 124736, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31494326

RESUMEN

In this work, a novel process involving the preparation of nanochitosan-grafted flocculants (CPAM-g-NCS) to treat low turbid and salmonella suspensions simultaneously was introduced. Nanotechnology was employed to enhance the adsorption-adhesion and sterilization abilities of dual-functional flocculants. The monomers of chitosan, acrylamide, methacryloyl ethyl trimethyl ammonium chloride, and sodium tripolyphosphate were utilized for flocculants copolymerization. Then, using fourier-transform infrared spectroscopy, nuclear magnetic resonance hydrogen spectrum, and thermogravimetric and differential scanning calorimetry analysis, the successful synthesis of CPAM-g-NCS was verified. Scanning electron microscopy and size analysis suggested that nanostructured flocculants with irregular morphology and nanocolloids of 60.44 nm were formed. CPAM-g-NCS was applied to treat a series of simulated low turbid and salmonella suspensions. The simulation results showed that the minimum residual turbidity of 1.97 NTU and optical density of 0.16 (initial 0.89) can be achieved at dosages of 2.5 and 8.75 mg L-1, respectively, which were superior to conventional organics flocculants. Mechanistic studies suggested that the excellent adsorption property, and large numbers of quaternary ammonium and amino groups of nanoflocculants contributed to the superior flocculation and antibacterial performance of CPAM-g-NCS.


Asunto(s)
Antiinfecciosos/química , Antiinfecciosos/farmacología , Nanoestructuras/química , Purificación del Agua/métodos , Acrilamida/química , Rastreo Diferencial de Calorimetría , Quitosano/química , Floculación , Espectroscopía de Resonancia Magnética , Metacrilatos/química , Microscopía Electrónica de Rastreo , Polimerizacion , Salmonella typhimurium/efectos de los fármacos , Espectroscopía Infrarroja por Transformada de Fourier , Suspensiones , Termogravimetría , Microbiología del Agua
9.
Int J Food Microbiol ; 312: 108387, 2020 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-31669763

RESUMEN

Fresh produce-associated outbreaks of foodborne illnesses continue to occur every year in the U.S., suggesting limitations of current practices and the need for effective intervention technologies. Advanced oxidation process involves production of hydrogen radicals, which are the strongest oxidant. The objective of the present study was to evaluate the effectiveness of advanced oxidation process by combining gaseous ozone and aerosolized hydrogen peroxide. Grape tomatoes were inoculated with a 2-strain cocktail of Salmonella typhimurium on both stem scar and smooth surface. Gaseous ozone (800 and 1600 ppm) and aerosolized hydrogen peroxide (2.5, 5 and 10%) were separately or simultaneously introduced into a treatment chamber where the inoculated tomatoes were placed. During the 30 min treatments, hydrogen peroxide was aerosolized using an atomizer operated in two modes: continuously or 15 s on/50 s off. After the treatments, surviving Salmonella on the smooth surface and stem scar were enumerated. Results showed that ozone alone reduced Salmonella populations by <0.6 log CFU/fruit on both the smooth surface and the stem scar area, and aerosolized hydrogen peroxide alone reduced the populations by up to 2.1 log CFU/fruit on the smooth surface and 0.8 log CFU/fruit on stem scar area. However, the combination treatments reduced the populations by up to 5.2 log CFU/fruit on smooth surface and 4.2 log CFU/fruit on the stem scar. Overall, our results demonstrate that gaseous ozone and aerosolized hydrogen peroxide have synergistic effects on the reduction of Salmonella populations on tomatoes.


Asunto(s)
Enfermedades Transmitidas por los Alimentos/prevención & control , Peróxido de Hidrógeno/farmacología , Lycopersicon esculentum/microbiología , Ozono/farmacología , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo , Recuento de Colonia Microbiana , Microbiología de Alimentos/métodos , Frutas/microbiología , Oxidación-Reducción
10.
Ultrason Sonochem ; 60: 104763, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31539729

RESUMEN

An investigation was conducted into the utilization of treatments combining ultrasound and lysozyme (US + Lys) to deactivate Salmonella typhimurium (S. typhimurium) in the liquid whole egg (LWE). Furthermore, US + Lys and heat treatment (HT) with a similar microbial inactivation effect were comparatively evaluated by examining their impact on the quality attributes of LWE. The LWE was treated with US at 35-45 °C and 605-968 W/cm2 for 5-35 min, and with HT at 58-64 °C for 3-4 min. Lysozyme (Lys) alone achieved a minimal degree of inactivation in S. typhimurium, while it was enhanced with the application of US alone when the treatment temperature, time, and energy were increased. Furthermore, US and US + Lys caused a reduction of 3.31 and 4.26 log10 cycles in S. typhimurium, respectively at 968 W/cm2 and 35 °C for 20 min, indicating a synergistic relationship between US and Lys for the effective inactivation of S. typhimurium. Similarly, HT and HT + Lys achieved a reduction of 4.10 and 4.75 log10 cycles at 64 °C/3 min, respectively. The L* and b* values of the LWE following US and US + Lys application were significantly higher than untreated and heat-treated LWE, indicating that US treated LWE had a brighter and yellower appearance. The protein solubility (PS) slightly decreased after all treatments, while the pH increased. Furthermore, the foaming capacity (FC) and foam stability (FS) were decreased, revealing that LWE had a lower FC and unstable foam after all treatments. Therefore, US and US + Lys could increase the viscosity and gelation temperature (Tg) of LWE, indicating that LWE exhibited higher heat resistance after US treatment. These results indicated that US + Lys might be a promising pasteurization technology in the processing of LWE.


Asunto(s)
Huevos/microbiología , Microbiología de Alimentos , Conservación de Alimentos , Muramidasa/farmacología , Salmonella typhimurium/efectos de los fármacos , Ondas Ultrasónicas , Recuento de Colonia Microbiana , Conservación de Alimentos/métodos , Viabilidad Microbiana , Reología
11.
Toxicol In Vitro ; 62: 104718, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31706955

RESUMEN

Ketamine is a potent uncompetitive NMDA receptor antagonist that provides amnesia, analgesia, environmental dissociation and immobility, where it has its cytotoxic effect well described in the literature. However, the work on its genotoxic/mutagenic potentials are scarce and insufficient and does not allow a reasonable evaluation of its role. Thus, in the present work, we decided to evaluate the genotoxic and mutagenic effects of ketamine on human peripheral blood leukocytes (PBLs) and Salmonella typhimurium (TA98, TA97a, TA100, and TA102) through several well-established experimental protocols based on different parameters in the presence or not of exogenous metabolizing S9 fraction. Our data revealed that ketamine induces a weak cytotoxic effect on human PBLs after 24 h and is devoided of hemolytic effects. A small amount of DNA strand breaks levels were detected in the modified comet assay (employment of FPG enzyme) only at highest concentrations (500 and 700 µg/mL) of ketamine, highlighting our pro-oxidant data regarding ketamine. However, the oxidative DNA lesions were almost completely repaired which reflects in the lack of mutagenesis (micronuclei and chromosomal aberrations) on human PBLs and no increases in revertants numbers on S. typhimurium/microsome test (500 to 5000 µg/plate). In summary, ketamine is a weak oxidative DNA damaging agent and is devoid of mutagenic properties on eukaryotic and prokaryotic models.


Asunto(s)
Anestésicos Disociativos/toxicidad , Ketamina/toxicidad , Leucocitos/efectos de los fármacos , Mutágenos/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Aberraciones Cromosómicas/inducido químicamente , Ensayo Cometa , Roturas del ADN , Daño del ADN , Hemólisis/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Pruebas de Mutagenicidad , Estrés Oxidativo
12.
J Ethnopharmacol ; 248: 112305, 2020 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-31639490

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: The development of selective inhibitors of monoamine oxidase B (MAO-B) has been essential in treating Parkinson's disease. However, the apparent hepatotoxicity and drug-drug interactions of current inhibitors accentuate the need for the development of novel pharmacotherapies. Crossyne guttata (L.) D. & U. Müll-Doblies is used frequently by Rastafarian bush doctors to treat alcoholism, a disorder which is also accentuated by MAO. OBJECTIVE: The study sought to isolate, identify and characterise the biologically active constituents of C. guttata based on their ability to inhibit the MAO enzymes. MATERIALS AND METHODS: Column chromatography was used to isolate the biologically active alkaloids of C. guttata. The ability of the alkaloids to inhibit the biotransformation of 4-aminoantipyrine by the MAO enzymes was evaluated in vitro. In silico docking was conducted using AutoDock Vina server while the pharmacokinetic properties of the compounds were evaluated using SwissADME. RESULTS: Chromatographic separation of an ethanolic fraction of C. guttata yielded the alkaloids crinamine 1 and epibuphanisine 2. 1 and 2 along with structurally related alkaloids haemanthamine 3 and haemanthidine 4 were evaluated for their ability to inhibit the action of isozymes of MAO in vitro. Alkaloids effected submicromolar IC50 values against MAO-B, the most potent of which being crinamine 1 (0.014 µM) > haemanthidine 4 (0.017 µM) > epibuphanisine 2 (0.039 µM) > haemanthamine 3 (0.112 µM). Binding energies of the alkaloids correlated well with their inhibitory potential with crinamine displaying the best binding efficacy and binding energy score with MAO-B. DISCUSSION AND CONCLUSION: Crinamine and epibuphanisine exhibited potent and selective inhibitory activity towards MAO-B. After comprehensive in silico investigations encompassing robust molecular docking analysis, the drug-like attributes and safety of the alkaloids suggest the crinamine is a potentially safe drug for human application.


Asunto(s)
Alcaloides de Amaryllidaceae/farmacología , Modelos Biológicos , Simulación del Acoplamiento Molecular , Inhibidores de la Monoaminooxidasa/farmacología , Monoaminooxidasa/metabolismo , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/farmacocinética , Alcaloides de Amaryllidaceae/toxicidad , Animales , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Humanos , Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacocinética , Inhibidores de la Monoaminooxidasa/toxicidad , Mutación , Seguridad del Paciente , Conformación Proteica , Medición de Riesgo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética , Relación Estructura-Actividad , Células Vero
13.
Food Chem Toxicol ; 134 Suppl 2: 111024, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31812735

RESUMEN

Hydroxycitronellal dimethyl acetal was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that hydroxycitronellal dimethyl acetal is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material and the exposure to hydroxycitronellal dimethyl acetal is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from hydroxycitronellal dimethyl acetal and from read-across material hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; hydroxycitronellal dimethyl acetal is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; hydroxycitronellal dimethyl acetal was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Asunto(s)
Acetales/toxicidad , Octanoles/toxicidad , Odorantes , Acetales/química , Animales , Seguridad de Productos para el Consumidor , Evaluación Preclínica de Medicamentos , Determinación de Punto Final , Escherichia coli/efectos de los fármacos , Humanos , Pruebas de Mutagenicidad , Nivel sin Efectos Adversos Observados , Octanoles/química , Medición de Riesgo , Salmonella typhimurium/efectos de los fármacos
14.
J Toxicol Sci ; 44(12): 871-876, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31813906

RESUMEN

Colibactin is a polyketide-peptide genotoxin produced by enteric bacteria such as E. coli, and is considered to contribute to the development of colorectal cancer. We previously isolated E. coli strains from Japanese colorectal cancer patients, and in the present study we investigated the genotoxic potency of the colibactin-producing (clb+) E. coli strains that carry the polyketide synthases "pks" gene cluster (pks+) and an isogenic clb- mutant in which the colibactin-producing ability is impaired. Measurement of phosphorylated histone H2AX indicated that DNA double strand breaks were induced in mammalian CHO AA8 cells infected with the clb+ E. coli strains. Induction of DNA damage response (SOS response) by crude extract of the clb+ strains was 1.7 times higher than that of the clb- E. coli in an umu assay with a Salmonella typhimurium TA1535/pSK1002 tester strain. Micronucleus test with CHO AA8 cells revealed that infection with the clb+ strains induced genotoxicity, i.e., the frequencies of micronucleated cells infected with clb+ strain were 4-6 times higher than with the clb- strain. Since the intestinal flora are affected by dietary habits that are strongly associated with ethnicity, these data may contribute to both risk evaluation and prevention of colorectal cancer in the Japanese population.


Asunto(s)
Colon/microbiología , Neoplasias Colorrectales/microbiología , Escherichia coli/aislamiento & purificación , Mutágenos/toxicidad , Péptidos/toxicidad , Policétidos/toxicidad , Anciano , Animales , Células CHO , Cricetulus , Roturas del ADN de Doble Cadena/efectos de los fármacos , Escherichia coli/genética , Escherichia coli/metabolismo , Humanos , Masculino , Micronúcleos con Defecto Cromosómico/inducido químicamente , Mutágenos/metabolismo , Péptidos/metabolismo , Policétidos/metabolismo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genética
15.
Food Chem Toxicol ; 134 Suppl 2: 111002, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31785315

RESUMEN

The existing information supports the use of this material as described in this safety assessment. p-Tolyl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl p-tolyl carbonate (CAS # 22719-81-9) show that p-tolyl acetate is not expected to be genotoxic. Data on read-across materials p-cresol (CAS # 106-44-5) and acetic acid (CAS # 64-19-7) provide a calculated MOE >100 for the repeated dose and reproductive toxicity endpoints. The skin sensitization endpoint was completed using DST for reactive materials (64 µg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; p-tolyl acetate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material, and the exposure to p-tolyl acetate is below the TTC (1.4 mg/day).The environmental endpoints were evaluated; p-tolyl acetate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


Asunto(s)
Cresoles/toxicidad , Odorantes , Animales , Seguridad de Productos para el Consumidor , Cresoles/química , Evaluación Preclínica de Medicamentos , Determinación de Punto Final , Escherichia coli/efectos de los fármacos , Humanos , Pruebas de Mutagenicidad , Nivel sin Efectos Adversos Observados , Medición de Riesgo , Salmonella typhimurium/efectos de los fármacos
16.
PLoS Pathog ; 15(12): e1008101, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31877175

RESUMEN

Active efflux due to tripartite RND efflux pumps is an important mechanism of clinically relevant antibiotic resistance in Gram-negative bacteria. These pumps are also essential for Gram-negative pathogens to cause infection and form biofilms. They consist of an inner membrane RND transporter; a periplasmic adaptor protein (PAP), and an outer membrane channel. The role of PAPs in assembly, and the identities of specific residues involved in PAP-RND binding, remain poorly understood. Using recent high-resolution structures, four 3D sites involved in PAP-RND binding within each PAP protomer were defined that correspond to nine discrete linear binding sequences or "binding boxes" within the PAP sequence. In the important human pathogen Salmonella enterica, these binding boxes are conserved within phylogenetically-related PAPs, such as AcrA and AcrE, while differing considerably between divergent PAPs such as MdsA and MdtA, despite overall conservation of the PAP structure. By analysing these binding sequences we created a predictive model of PAP-RND interaction, which suggested the determinants that may allow promiscuity between certain PAPs, but discrimination of others. We corroborated these predictions using direct phenotypic data, confirming that only AcrA and AcrE, but not MdtA or MsdA, can function with the major RND pump AcrB. Furthermore, we provide functional validation of the involvement of the binding boxes by disruptive site-directed mutagenesis. These results directly link sequence conservation within identified PAP binding sites with functional data providing mechanistic explanation for assembly of clinically relevant RND-pumps and explain how Salmonella and other pathogens maintain a degree of redundancy in efflux mediated resistance. Overall, our study provides a novel understanding of the molecular determinants driving the RND-PAP recognition by bridging the available structural information with experimental functional validation thus providing the scientific community with a predictive model of pump-contacts that could be exploited in the future for the development of targeted therapeutics and efflux pump inhibitors.


Asunto(s)
Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Proteínas de Transporte de Membrana/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Infecciones Bacterianas/tratamiento farmacológico , Proteínas Bacterianas/efectos de los fármacos , Proteínas Bacterianas/metabolismo , Transporte Biológico/efectos de los fármacos , Proteínas Portadoras/metabolismo , Femenino , Proteínas de Transporte de Membrana/metabolismo , Ratones Endogámicos BALB C , Periplasma/efectos de los fármacos , Periplasma/metabolismo , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/metabolismo
17.
J Food Sci ; 84(12): 3700-3706, 2019 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-31721204

RESUMEN

The antibacterial effects of ultrasound (US) and cinnamon essential oil (CEO), individually and combined, were investigated against Listeria monocytogenes and Salmonella Typhimurium in low- and high-fat milk during 6-day storage. At the end of storage, CEO alone decreased 2 and 2.2 log cycles of Salmonella Typhimurium and 2.5 and 3 log cycles of L. monocytogenes populations in low- and high-fat milk, respectively. US alone reduced 1.6 log cycle of Salmonella Typhimurium and 0.7 log cycle of L. monocytogenes in both milk type. The combined treatment could reduce 2.7 log cycle of Salmonella Typhimurium in low-fat milk and 3.8 log cycle in high-fat milk. The combined treatment also achieved 4.3 and 4.5 log cycle reductions of L. monocytogenes in low- and high-fat milk, respectively. The results of this study showed that the combination of CEO and US could be used as an effective antibacterial treatment in milk. PRACTICAL APPLICATIONS: Due to adverse effects of thermal processing on the sensory and nutritional properties of food and the potentially harmful effects of chemical preservatives, nonthermal preservation methods and natural antimicrobials have been gained much attention. In this study, the antibacterial effects of ultrasound (US) and cinnamon essential oil (CEO), individually and combined, were investigated against Listeria monocytogenes and Salmonella Typhimurium in low- and high-fat milk. The results indicated that combination of US and CEO could significantly decrease L. monocytogenes and Salmonella Typhimurium populations in milk. Then, this combined treatment may be used as an effective alternative method to microbial inactivation in milk.


Asunto(s)
Antibacterianos/farmacología , Cinnamomum zeylanicum/química , Conservación de Alimentos/métodos , Leche/microbiología , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Ultrasonido/métodos , Animales , Antibacterianos/aislamiento & purificación , Bovinos , Recuento de Colonia Microbiana , Conservación de Alimentos/instrumentación , Listeria monocytogenes/efectos de los fármacos , Listeria monocytogenes/crecimiento & desarrollo , Viabilidad Microbiana/efectos de los fármacos , Leche/química , Aceites Volátiles/aislamiento & purificación , Extractos Vegetales/aislamiento & purificación , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/crecimiento & desarrollo
20.
Mutat Res ; 847: 503095, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31699345

RESUMEN

I first became acquainted with the Ames test at the very beginning of my career in 1978, when my task at the National Institute of Health Sciences (Tokyo) was to screen for mutagenicity of food additives used in Japan, using the Ames test. I also used this test to research the metabolic activation mechanisms of chemical carcinogens, in particular, the analgesic drug, phenacetin. This chemical was not mutagenic in Salmonella typhimurium TA100 with standard 9000 × g supernatant of liver homogenates (S9) from rat but was mutagenic with hamster S9. It was revealed that hamster S9 had much higher deacetylation activities than rat S9, which accounts for the species difference. Then, my work was focused on molecular biology. We cloned the genes encoding nitroreductase and acetyltransferase in Salmonella typhimurium TA1538. Plasmids carrying these genes made strain TA98 more sensitive to mutagenic nitroarenes and aromatic amines. Because of their high sensitivity, the resulting strains such as YG1021 and YG1024 are widely used to monitor mutagenic nitroarenes and aromatic amines in complex mixtures. Later, we disrupted the genes encoding DNA polymerases in TA1538 and classified chemical mutagens into four classes depending on their use of different DNA polymerases. I was also involved in the generation of gpt delta transgenic rodent gene mutation assays, which examine the results of the Ames test in vivo. I have unintentionally developed my career under the influence of Dr. Ames and I would like to acknowledge his remarkable achievements in the field of environmental mutagenesis and carcinogenesis.


Asunto(s)
Pruebas de Mutagenicidad , Salmonella typhimurium/efectos de los fármacos , Activación Metabólica , Animales , Animales Modificados Genéticamente , Animales Endogámicos , Proteínas Bacterianas/metabolismo , Boston , Carcinógenos/farmacocinética , Carcinógenos/toxicidad , Clonación Molecular , Cricetinae , ADN Polimerasa Dirigida por ADN/metabolismo , Exposición a Riesgos Ambientales/legislación & jurisprudencia , Escherichia coli/enzimología , Proteínas de Escherichia coli/genética , Femenino , Aditivos Alimentarios/farmacocinética , Aditivos Alimentarios/toxicidad , Japón , Ratones , Microsomas Hepáticos/metabolismo , Mutágenos/farmacocinética , Mutágenos/toxicidad , Pentosiltransferasa/genética , Ratas , Proteínas Recombinantes/metabolismo , Salmonella typhimurium/clasificación , Salmonella typhimurium/enzimología , Salmonella typhimurium/genética
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