ABSTRACT
BACKGROUND The massive use of insecticides in public health has exerted selective pressure resulting in the development of resistance in Aedes aegypti to different insecticides in Venezuela. Between 2010 and 2020, the only insecticides available for vector control were the organophosphates (Ops) fenitrothion and temephos which were focally applied. OBJECTIVES To determine the state of insecticide resistance and to identify the possible biochemical and molecular mechanisms involved in three populations of Ae. aegypti from Venezuela. METHODS CDC bottle bioassays were conducted on Ae. aegypti collected between October 2019 and February 2020 in two hyperendemic localities for dengue in Aragua State and in a malaria endemic area in Bolívar State. Insecticide resistance mechanisms were studied using biochemical assays and polymerase chain reaction (PCR) to detect kdr mutations. FINDINGS Bioassays showed contrasting results among populations; Las Brisas was resistant to malathion, permethrin and deltamethrin, Urbanización 19 de Abril was resistant to permethrin and Nacupay to malathion. All populations showed significantly higher activity of mixed function oxidases and glutathione-S-transferases (GSTs) in comparison with the susceptible strain. The kdr mutations V410L, F1534C, and V1016I were detected in all populations, with F1534C at higher frequencies. MAIN CONCLUSION Insecticide resistance persists in three Ae. aegypti populations from Venezuela even in the relative absence of insecticide application.
ABSTRACT
Mosquitoes belonging to the genus Aedes pose a significant threat to human health on a global scenario due to their role in transmission of dengue, chikungunya, zika, and yellow fever. In absence of specific medications and vaccines against these diseases, disease prevention relies on vector control. However, in today's world, vector control is facing major challenges due to the onset of insecticide resistance in mosquitoes. There are four main mechanisms of insecticide resistance, namely, behavioral resistance, reduced penetration/cuticular resistance, metabolic detoxification, and target site resistance; however, the latter two mechanisms have been studied widely in Aedes mosquitoes. Insecticide resistance in Aedes mosquitoes is widespread throughout the world. This review compiles the degree of insecticide resistance/susceptibility prevailing among different field populations of Aedes mosquitoes worldwide. In addition, the review has detailed the mechanisms providing the resistance phenomenon observed in nature in Aedes mosquitoes.
ABSTRACT
Unsymmetrical bisacridines (UAs) are a novel potent class of antitumor-active therapeutics.A significant route of phase II drug metabolism is conjugation with glutathione (GSH),which can be non-enzymatic and/or catalyzed by GSH-dependent enzymes.The aim of this work was to investigate the GSH-mediated metabolic pathway of a representative UA,C-2028.GSH-supplemented incubations of C-2028 with rat,but not with human,liver cytosol led to the formation of a single GSH-related metabolite.Interestingly,it was also revealed with rat liver microsomes.Its formation was NADPH-independent and was not inhibited by co-incubation with the cytochrome P450 (CYP450) inhibitor 1-aminobenzotriazole.Therefore,the direct conjugation pathway occurred without the prior CYP450-catalyzed bioactivation of the substrate.In turn,incubations of C-2028 and GSH with human recombinant glutathione S-transferase(GST) P1-1 or with heat-/ethacrynic acid-inactivated liver cytosolic enzymes resulted in the presence or lack of GSH conjugated form,respectively.These findings proved the necessary participation of GST in the initial activation of the GSH thiol group to enable a nucleophilic attack on the substrate molecule.Another C-2028-GSH S-conjugate was also formed during non-enzymatic reaction.Both GSH S-conju-gates were characterized by combined liquid chromatography/tandem mass spectrometry.Mechanisms for their formation were proposed.The ability of C-2028 to GST-mediated and/or direct GSH conjugation is suspected to be clinically important.This may affect the patient's drug clearance due to GST activity,loss of GSH,or the interactions with GSH-conjugated drugs.Moreover,GST-mediated depletion of cellular GSH may increase tumor cell exposure to reactive products of UA metabolic transformations.
ABSTRACT
Con el propósito de evaluar el efecto de un secuestrante comercial de micotoxinas (SM) con base en glucomananos, sobre la producción de gas y degradación ruminal in vitro, se incubó harina de granos de maíz (Zea mayz L.) en licor ruminal con concentraciones de aflatoxina B1 (AFB1) de 4, 8 y 12 ppb, respectivamente, y proporciones de AFB1: SM de 1:75000 (SM-75), 1:150000 (SM-150) y 1:225000 (SM-225). Adicionalmente, se consideró un tratamiento sin inclusión del secuestrante de micotoxinas (SM-0). La producción de gas se registró a las 3, 6, 9, 12, 16 y 24 h, y la actividad del SM a las 3 h de incubación. La información fue analizada utilizando un diseño completamente aleatorizado con arreglo factorial 3x4. La concentración de AFB1 afectó negativamente (P<0,05) la producción de gas, con el mayor impacto a las 9 h, cuando 12 ppb [5,15 mL/g de materia seca (MS)] generaron una reducción en la producción de gas, en comparación con 4 y 8 ppb (6,57 y 6,01 mL/g MS), respectivamente. Independientemente del nivel utilizado y luego de 24 h de incubación, el uso de SM incrementó (P<0,05) la producción de gas respecto al SM-0 en 25,5% (68,5 vs. 56,6 mL/g MS, respectivamente). En todos los tratamientos, SM-75 mostró la mayor producción de gas, sin mejoras debido a aumentos adicionales en la relación SM:AFB1. La concentración de AFB1 afectó (P<0,05) negativamente la degradación de la MS de la harina de maíz, con una reducción del 39,8%, luego de 12 h de incubación. La capacidad secuestrante fue del 86,0 ± 3,34%, sin diferencias (P>0,05) debida al nivel de AFB1 o a la relación AFB1:SM. Estos resultados demuestran que el aditivo biotecnológico evaluado, reduce el impacto negativo de la AFB1 sobre la producción ruminal in vitro de gas y la degradación aparente de la MS.
To evaluate the effect of a commercial mycotoxin binder (MB) based on glucomannans, on the in vitro gas production and ruminal degradation, maize (Zea mayz L.) grain meal was incubated in ruminal liquor with aflatoxin B1 (AFB1) concentrations of 4, 8 y 12, respectively, and proportions of AFB1: MB of 1:75000 (MB-75), 1:150000 (MB-150), and 1:225000 (MB-225). Additionally, a treatment without MB was considered (MB-0). Gas production was measured at 3, 6, 9, 12, 16, and 24 h, and MB activity after 3 h of incubation. Data was analyzed using a completely randomized design with a 3x4 factorial arrangement. The results show that gas production was negatively affected by AFB1 concentration (P<0.05), with the higher impact at 9 h, when 12 ppb [5.15 mL/g of dry matter (DM)] generated a reduction, when compared to 4 and 8 ppb (6.57 and 6.01 mL/g of DM, respectively). Regardless of the level used and after 24 h of incubation, the use of MB increased (P<0.05) gas production in 25.5%, compared to SM-0 (68.5 vs. 56.6 mL/g of DM, respectively). In all treatments, MB-75 showed the highest gas production without improvements, due to further increases in the ratio MB: AFB1. The AFB1 concentration negatively affected (P <0.05) degradation of DM of maize meal, with a reduction of 39.8%, after 12 h of incubation. The binding capacity was 86.0 ± 3.34%, without differences (P<0.05) due to AFB1 concentration or AFB1: MB relation. These results demonstrate that the assessed biotechnological additive reduces the negative impact of AFB1 on the in vitro ruminal gas production and apparent DM degradation.