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1.
PLoS Comput Biol ; 20(2): e1011375, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38381804

RESUMEN

The rapid intensification of poultry production raises important concerns about the associated risks of zoonotic infections. Here, we introduce EPINEST (EPIdemic NEtwork Simulation in poultry Transportation systems): an agent-based modelling framework designed to simulate pathogen transmission within realistic poultry production and distribution networks. We provide example applications to broiler production in Bangladesh, but the modular structure of the model allows for easy parameterization to suit specific countries and system configurations. Moreover, the framework enables the replication of a wide range of eco-epidemiological scenarios by incorporating diverse pathogen life-history traits, modes of transmission and interactions between multiple strains and/or pathogens. EPINEST was developed in the context of an interdisciplinary multi-centre study conducted in Bangladesh, India, Vietnam and Sri Lanka, and will facilitate the investigation of the spreading patterns of various health hazards such as avian influenza, Campylobacter, Salmonella and antimicrobial resistance in these countries. Furthermore, this modelling framework holds potential for broader application in veterinary epidemiology and One Health research, extending its relevance beyond poultry to encompass other livestock species and disease systems.


Asunto(s)
Epidemias , Gripe Aviar , Animales , Aves de Corral , Pollos , Gripe Aviar/epidemiología , Zoonosis/epidemiología
2.
Biomed Chromatogr ; : e5939, 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38886169

RESUMEN

The presence of undesired agrochemicals residues in soil and water poses risks to both human health and the environment. The behavior of pesticides in soil depends both on the physico-chemical properties of pesticides and soil type. This study examined the adsorption-desorption and leaching behavior of the maize herbicide tembotrione in soils of the upper (UGPZ), trans (TGPZ) and middle Gangetic plain zones of India. Soil samples were extracted using acetone followed by partitioning with dichloromethane, whereas liquid-liquid extraction using dichloromethane was used for aqueous samples. Residues of tembotrione and its metabolite TCMBA, {2-chloro-4-(methylsulfonyl)-3-[(2,2,2-trifluoroethoxy) methyl] benzoic acid}, were quantified using liquid chromatography-tandem mass spectrometry. The data revealed that tembotrione adsorption decreased with increasing pH and dissolved organic matter but increased with salinity. The maximum adsorption occurred at pH 4, 0.01 m sodium citrate and 4 g/L NaCl, with corresponding Freundlich constants of 1.83, 2.28 and 3.32, respectively. The hysteresis index <1 indicated faster adsorption than desorption. Leaching studies under different flow conditions revealed least mobility in UGPZ soil and high mobility in TGPZ soil, consistent with groundwater ubiquity scores of 4.27 and 4.81, respectively. Soil amendments decreased tembotrione mobility in the order: unamended > wheat straw ash > wheat straw > farm yard manure > compost. The transformation of tembotrione to TCMBA and its mobility in soil columns were also assessed.

3.
Proc Natl Acad Sci U S A ; 117(36): 22357-22366, 2020 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-32839313

RESUMEN

Fever is a conserved and prominent response to infection. Yet, the issue of how CD4 T cell responses are modulated if they occur at fever temperatures remains poorly addressed. We have examined the priming of naive CD4 T cells in vitro at fever temperatures, and we report notable fever-mediated modulation of their cytokine commitment. When naive CD4 T cells were primed by plate-bound anti-CD3 and anti-CD28 monoclonal antibodies at moderate fever temperature (39 °C), they enhanced commitment to IL4/5/13 (Th2) and away from IFNg (Th1). This was accompanied by up-regulation of the Th2-relevant transcription factor GATA3 and reduction in the Th1-relevant transcription factor Tbet. Fever sensing by CD4 T cells involved transient receptor potential vanilloid cation channels (TRPVs) since TRPV1/TRPV4 antagonism blocked the febrile Th2 switch, while TRPV1 agonists mediated a Th2 switch at 37 °C. The febrile Th2 switch was IL4 independent, but a γ-secretase inhibitor abrogated it, and it was not found in Notch1-null CD4 T cells, identifying the Notch pathway as a major mediator. However, when naive CD4 T cells were primed via antigen and dendritic cells (DCs) at fever temperatures, the Th2 switch was abrogated via increased production of IL12 from DCs at fever temperatures. Thus, immune cells directly sense fever temperatures with likely complex physiological consequences.


Asunto(s)
Linfocitos T CD4-Positivos/fisiología , Diferenciación Celular/fisiología , Fiebre/fisiopatología , Receptores Notch/metabolismo , Canales Catiónicos TRPV/metabolismo , Animales , Temperatura Corporal/fisiología , Linfocitos T CD4-Positivos/citología , Células Cultivadas , Calor , Ratones , Modelos Biológicos
4.
Int J Mol Sci ; 23(24)2022 Dec 16.
Artículo en Inglés | MEDLINE | ID: mdl-36555660

RESUMEN

Protein synthesis is tightly regulated by both gene-specific and global mechanisms to match the metabolic and proliferative demands of the cell. While the regulation of global protein synthesis in response to mitogen or stress signals is relatively well understood in multiple experimental systems, how different cell types fine-tune their basal protein synthesis rate is not known. In a previous study, we showed that resting B and T lymphocytes exhibit dramatic differences in their metabolic profile, with implications for their post-activation function. Here, we show that resting B cells, despite being quiescent, exhibit increased protein synthesis in vivo as well as ex vivo. The increased protein synthesis in B cells is driven by mTORC1, which exhibits an intermediate level of activation in these cells when compared with resting T cells and activated B cells. A comparative analysis of the transcriptome and translatome of these cells indicates that the genes encoding the MHC Class II molecules and their chaperone CD74 are highly translated in B cells. These data suggest that the translatome of B cells shows enrichment for genes associated with antigen processing and presentation. Even though the B cells exhibit higher mTORC1 levels, they prevent the translational activation of TOP mRNAs, which are mostly constituted by ribosomal proteins and other translation factors, by upregulating 4EBP1 levels. This mechanism may keep the protein synthesis machinery under check while enabling higher levels of translation in B cells.


Asunto(s)
Biosíntesis de Proteínas , Proteínas Ribosómicas , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Proteínas Ribosómicas/metabolismo , Linfocitos T , Linfocitos B
5.
Biomed Chromatogr ; 35(12): e5213, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34227143

RESUMEN

Cyantraniliprole is an anthranilic diamide insecticide used for the effective management of diamondback moth in cabbage. Dietary risk assessment of pesticides in food is a major concern now. This study developed a QuEChERS/HPLC-PDA-based highly efficient and reliable method, registering 89.80-100.11% recoveries of cyantraniliprole and its metabolite IN-J9Z38 from cabbage and soil with a relative standard deviation of 0.43-5.77%. Field experiment was conducted to study the residue dissipation of cyantraniliprole in cabbage and soil. Two foliar treatments of 10.26% formulation (Benevia) at 60 (T1 ) and 120 (T2 ) gram active ingredient/hectare were applied. The dissipation half-lives of cyantraniliprole in cabbage and soil were determined to be 3.5-4.2 and 3.8-5.3 days at T1 and 3.9-4.8 and 4.1-4.7 days at T2 , respectively. The maximum concentrations of IN-J9Z38 at T1 and T2 were 0.819 and 1.061 mg/kg, respectively, on the fifth day. A risk quotient value of <1 indicates no dietary risk to the consumers. The residues in the harvested cabbage were below the tolerance level of 2.0 mg/kg established by the regulatory body in India.


Asunto(s)
Brassica/química , Insecticidas , Residuos de Plaguicidas , Pirazoles , Contaminantes del Suelo , ortoaminobenzoatos , Brassica/efectos de los fármacos , Cromatografía Líquida de Alta Presión/métodos , Dieta , Humanos , Insecticidas/análisis , Insecticidas/farmacocinética , Insecticidas/toxicidad , Modelos Biológicos , Residuos de Plaguicidas/análisis , Residuos de Plaguicidas/farmacocinética , Residuos de Plaguicidas/toxicidad , Pirazoles/análisis , Pirazoles/farmacocinética , Pirazoles/toxicidad , Medición de Riesgo , Contaminantes del Suelo/análisis , Contaminantes del Suelo/farmacocinética , Contaminantes del Suelo/toxicidad , ortoaminobenzoatos/análisis , ortoaminobenzoatos/farmacocinética , ortoaminobenzoatos/toxicidad
6.
J Anaesthesiol Clin Pharmacol ; 37(2): 216-220, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34349369

RESUMEN

BACKGROUND AND AIMS: Lumbar epidural catheter insertion is conventionally performed by anesthesia residents by palpation of anatomical landmarks with relatively blind localization of epidural space which may lead to an increase in failure rate. We aim to compare the ease of lumbar epidural catheterization using prepuncture ultrasound as guidance with that of conventional palpatory technique. Comparisons were made with reference to number of insertion attempts, total time taken for the procedure, frequency of dural puncture, and overall satisfaction score as assessed by Likert's scale. MATERIAL AND METHODS: Eighty, ASA 1-3, patients undergoing elective surgeries requiring lumbar epidural catheterization were recruited for the study. Study participants were randomized into two groups. In group P, epidural catheterization was performed using the conventional palpatory method and in group U, it was performed with the help of ultrasound determined parameters. Number of insertion attempts, total time taken for successful insertion of epidural catheter, frequency of dural puncture, and overall satisfaction of ease of insertion as determined by Likert's scale were compared between both the groups. Data were analyzed using SPSS statistical software version 17 and P value <0.05 was considered statistically significant. RESULTS: The number of insertion attempts was significantly lesser in Group U (P = 0.019). The total procedure time was significantly higher in group U (P < .001). There was no significant difference in ease of insertion score, as measured by Likert's scale between both the groups (P = 0.45). CONCLUSION: Prepuncture ultrasound guidance improves the first attempt success rate of lumbar epidural catheterization with reduced incidence of dural puncture with similar overall satisfaction score but increases the total time taken for the procedure when compared to conventional palpatory technique.

7.
Immunology ; 160(3): 295-309, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32187647

RESUMEN

Activated T-cells make both interleukin-2 (IL2) and its high-affinity receptor component CD25. Regulatory CD4 T-cells (Treg cells) do not make IL2, and the IL2-CD25 circuit is considered a paracrine circuit crucial in their generation and maintenance. Yet, all T-cells are capable of making IL2 at some stage during differentiation, making a cell-intrinsic autocrine circuit additionally possible. When we re-visited experiments with mixed bone marrow chimeras using a wide range of ratios of wild-type (WT) and IL2-/- genotype progenitors, we found that, as expected, thymic Treg cells were almost equivalent between WT and IL2-/- genotypes at ratios with WT prominence. However, at WT-limiting ratios, the IL2-/- genotype showed lower thymic Treg frequencies, indicating a role for cell-intrinsic autocrine IL2 in thymic Treg generation under IL2-limiting conditions. Further, peripheral IL2-/- naive CD4 T-cells showed poor conversion to inducible Tregs (pTregs) both in vivo and in vitro, again indicating a significant role for cell-intrinsic autocrine IL2 in their generation. Peripherally, the IL2-/- genotype was less prominent at all WT:IL2-/- ratios among both thymic Tregs (tTregs) and pTregs, adoptively transferred IL2-/- Tregs showed poorer survival than WT Tregs did, and RNA-seq analysis of WT and IL2-/- Tregs showed interesting differences in the T-cell receptor and transforming growth factor-beta-bone morphogenetic protein-JNK pathways between them, suggesting a non-titrating role for cell-intrinsic autocrine IL2 in Treg programming. These data indicate that cell-intrinsic autocrine IL2 plays significant roles in Treg generation and maintenance.


Asunto(s)
Interleucina-2/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Comunicación Autocrina , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Homeostasis , Interleucina-2/genética , Activación de Linfocitos , MAP Quinasa Quinasa 4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Quimera por Trasplante
8.
J Environ Sci Health B ; 55(12): 1032-1040, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32811281

RESUMEN

In the present work, persistence and degradation of cyantraniliprole, a leading anthranilic diamide pesticide against sucking insect pests, in inceptisol soil has been studied. Effect of various factors like light source (UV-light, sunlight and dark), temperature (5, 25 and 37 °C), moisture regime (dry, field capacity and submerged) and carbon dioxide level (415 and 625 µL L-1) on dissipation was also evaluated. Formation of IN-J9Z38, a major metabolite of cyantraniliprole, was monitored in different treatments. Samples were processed as per QuEChERS method and analysis was done by HPLC-PDA. Matrix matched calibration curve, prepared in the range 0.001-10 mg L-1, indicated very good linearity (R2 > 0.99) and sensitivity (instrument limit of detection 0.001 mg L-1). Cyantraniliprole residues dissipated with time and 47.7%-98.8% dissipation was recorded on 90th day in different treatments. Minimum half-life of cyantraniliprole, i.e. 8.7 days was recorded at elevated CO2 level (625 ± 5 µL L-1) while its maximum half-life of 86.6 days was recorded at 5 °C. Metabolite IN-J9Z38 started forming from zero-day and reached the maximum on 15th to 60th day. Microbial biomass carbon, as an index of microbial activity of soil, correlated well with the degradation of cyantraniliprole.


Asunto(s)
Dióxido de Carbono , Pirazoles/química , Contaminantes del Suelo/química , ortoaminobenzoatos/química , Biodegradación Ambiental , Calibración , Dióxido de Carbono/análisis , Cromatografía Líquida de Alta Presión/métodos , Semivida , Insecticidas/análisis , Insecticidas/química , Insecticidas/metabolismo , Límite de Detección , Pirazoles/análisis , Pirazoles/metabolismo , Sensibilidad y Especificidad , Suelo/química , Microbiología del Suelo , Contaminantes del Suelo/análisis , Contaminantes del Suelo/metabolismo , Luz Solar , Temperatura , Factores de Tiempo , Rayos Ultravioleta , ortoaminobenzoatos/análisis , ortoaminobenzoatos/metabolismo
9.
Bull Environ Contam Toxicol ; 104(4): 503-510, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32064538

RESUMEN

Kresoxim methyl sorption in soils of five agro-climatic zones of India varied from 41.6% to 84.7%. Highest sorption was recorded in organic carbon rich Almora soil. Isotherm parameters for linear and non-linear Freundlich and Temkin models were almost same, whereas Langmuir parameter Q0, for linear (1.60 to 9.434 µg g-1) and non-linear (8.48 to 17.129 µg g-1) models were quite different. For isotherms optimization different error functions such as sum of squares error (SSE), root mean square error (RMSE), Chi square error, hybrid fractional error (HYBRID) and average relative error (ARE) were calculated. Lowest error function values were obtained for Freundlich isotherm in all the soils except inceptisol (Kolkata) for which Langmuir isotherm gave the best fit. Statistical analysis using SAS 9.3 software and Tukey's HSD test revealed the significant effect (p < 0.001) of soil type on sorption. Sorption correlated positively with the organic carbon and clay contents of the soil.


Asunto(s)
Monitoreo del Ambiente/métodos , Modelos Teóricos , Contaminantes del Suelo/análisis , Suelo/química , Estrobilurinas/análisis , Adsorción , Agricultura , India , Modelos Lineales , Dinámicas no Lineales
10.
Immunology ; 158(1): 19-34, 2019 09.
Artículo en Inglés | MEDLINE | ID: mdl-31215020

RESUMEN

Studies with gene-deficient and gnotobiotic mice have identified many host and microbial factors that contribute to induced colitis, but information on whether specific factors determine susceptibility under more physiological conditions is lacking. Using wild-type strains that differ in their IgA response but harbor a diverse gut microbiome, we found that the IgA-high strain CBA/CaJ (CBA) is resistant to acute colitis induced with dextran sodium sulfate (DSS), unlike the IgA-low strain C57BL/6 (B6). Resistance was associated with extensive IgA-coating of fecal bacteria, lower fecal bacterial loads and greater abundance of barrier-protective transcripts in colonic tissues under homeostatic conditions. Fecal microbial transplant (FT) experiments revealed that disease induction in B6 mice was associated with a cohort of bacteria that are not targeted by IgA. However, CBA mice continued to be resistant to colitis induction following FTs from B6 mice, indicating that they are able to contain such colitogenic members. In support of a role for bacterial exclusion in resistance, oral administration of immunoglobulins decreased DSS-induced disease in B6 mice. In F1 mice derived separately with CBA and B6 dams and in F1 mice backcrossed to the two parental strains, resistance segregated with the IgA response of the pups and not with barrier-associated transcripts or bacterial loads. Interestingly, B6 pups foster-nursed on CBA dams continued to be susceptible in later life, whereas CBA pups foster-nursed on B6 dams continued to be resistant. Together, the data indicate that a high-IgA response in adult life can protect against colitis and compensate for IgA deficiency in early life.


Asunto(s)
Bacterias/inmunología , Colitis/prevención & control , Colon/microbiología , Sulfato de Dextran , Microbioma Gastrointestinal/inmunología , Inmunoglobulina A/inmunología , Animales , Animales Recién Nacidos , Carga Bacteriana , Colitis/inducido químicamente , Colitis/inmunología , Colitis/microbiología , Colon/inmunología , Colon/metabolismo , Cruzamientos Genéticos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Heces/microbiología , Femenino , Inmunoglobulina A/metabolismo , Mediadores de Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Lactancia , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Endogámicos DBA , Permeabilidad , Embarazo , Especificidad de la Especie
11.
Environ Monit Assess ; 191(11): 670, 2019 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-31650309

RESUMEN

An analytical method involving modified QuEChERS (quick, easy, cheap, effective, rugged and safe) technique coupled with LC-MS/MS (liquid chromatography-tandem mass spectroscopy) has been developed for simultaneous identification and quantification of 71 pesticides (insecticides/acaricides/nematicides (32), fungicides (12), herbicides (26), plant growth regulator (1)) in different pulses (edible seeds of leguminous plants), namely gram, lentil, black gram and pea. The analysis was done using Shimadzu LC-MS/MS-8030 instrument equipped with Zorbax Eclipse Plus C-18 column operating under electrospray ionization (ESI) in positive and negative modes. Validation of method was done as per a single laboratory validation approach. Nine-point linear calibration curves for each pesticide were obtained in the range of 0.005 to 2 µg/g with correlation coefficient of ≥ 0.98. Limit of detection (LOD) for all the pesticides was achieved in the range of 0.001-0.015 µg/g, whereas the limit of quantification (LOQ) were found in the range of 0.01-0.05 µg/g. Recovery studies were conducted at 0.01- and 0.05-µg/g level of fortification using modified buffered QuEChERS method standardized for low moisture foods. It was observed that due to matrix interference, only around 75% of the pesticides were recovered in an acceptable range of 70-120% when compared against the solvent standard. With matrix-matched standards, 95% of the recovery results came within acceptable range with highly acceptable HorRat ratio (between 0.2 and 0.8) indicating satisfactory precision. The global and expanded uncertainties for estimation of each pesticide in above-mentioned pulse matrices were calculated to evaluate the suitability of the developed method for quantification of pesticides in pulse matrices.


Asunto(s)
Monitoreo del Ambiente/métodos , Fungicidas Industriales/análisis , Herbicidas/análisis , Insecticidas/análisis , Residuos de Plaguicidas/análisis , Verduras/química , Cromatografía Liquida/métodos , Protección de Cultivos , Límite de Detección , Semillas/química , Espectrometría de Masas en Tándem/métodos
12.
J Anaesthesiol Clin Pharmacol ; 35(2): 236-241, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31303715

RESUMEN

BACKGROUND AND AIMS: Early psychomotor recovery is an essential part of day care surgery which depends on brain integration of motor and sensory co-ordination. Even though dexmedetomidine is commonly used for day care procedures, the recovery profile was not studied. Hence, this study was designed to evaluate the psychomotor recovery of sedation with dexmedetomidine during spinal anesthesia. MATERIAL AND METHODS: Sixty-six patients were included. Group D received dexmedetomidine 0.5 µg/kg (loading dose) followed by 0.2-1 µg/kg/hour. Group P received propofol infusion of 25-100 µg/kg/minute. Psychomotor recovery was assessed by finger-tapping, manual dexterity, visual spatial memory capacity, and pen and paper tests. Psychomotor tasks were given to the patients postoperatively at every 30 minutes for 2 hours followed by every hour up to 4 hours after surgery. Distribution of patients, age, weight, duration of surgery, and the level of sensory blockade was compared using independent t-test. Student's t-test has been used to find the significance of parameters such as heart rate, mean arterial pressure, oxygen saturation (SpO2), psychomotor recovery between two groups. P < 0.05 was considered as significant. RESULTS: The motor recovery using finger tapping test was faster in Group D than Group P (73.94 ± 42.13 vs 101.21 ± 37.98 minutes, P-value = 0.007). Motor recovery using peg board test was faster in Group P than Group D (82.12 ± 40.37 vs 99.39 ± 43.08 minutes, P-value = 0.098). Visual spatial capacity memory test and pen and paper test were unaffected. CONCLUSIONS: We conclude that patients who received dexmedetomidine showed earlier recovery with finger tapping test. Hence, we suggest to use dexmedetomidine for complete psychomotor recovery and fast-track discharging of the patient after spinal anesthesia.

13.
Exp Appl Acarol ; 75(3): 319-331, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29846851

RESUMEN

The frequently used chemical control method to manage Rhipicephalus microplus is limited by the emergence of resistance populations. Understanding of resistance mechanisms is essential to develop strategy for sustainable management. The present study was focused on working out the molecular mechanisms of resistance against synthetic pyrethroids (SPs) and organophosphates (OPs) in field isolates of R. microplus collected from six districts of Uttar Pradesh, India. Adult immersion test with discriminating concentrations (AIT-DC) was used to determine resistance status of isolates to SPs (deltamethrin, cypermethrin) and OPs (diazinon, coumaphos). All the six isolates were found resistant to SPs with resistance factor (RF) of 2.9-58.6 and to one of the OP compounds, diazinon having RF of 3.5-13.7 but susceptible to coumaphos (RF < 1.4). Three R. microplus genes, viz. para-sodium channel domain II S4-5 linker, carboxylesterase (372 bp) and acetylcholinesterase 2 (1692 bp) were sequenced and compared with respective sequences of reference susceptible IVRI-I, reference OP resistant population (IVRI-III), IVRI-IV and multi-acaricide resistant population (IVRI-V) of R. microplus. A C190A mutation in the domain II S4-5 linker region of sodium channel gene leading to L64I amino acid substitution was detected in all six isolates. The G1120A mutation in the carboxylesterase gene could not be detected in any isolate. Five nucleotide substitutions viz., G138A, G889A, T1090A, C1234T and G1403A were identified in the acetylcholinesterase 2 gene leading to four amino acid substitutions. The findings of the study corroborate the role of mutation in sodium channel and acetylcholinesterase 2 genes in SP and OP resistance in this part of India.


Asunto(s)
Acaricidas/toxicidad , Organofosfatos/toxicidad , Piretrinas/toxicidad , Rhipicephalus/efectos de los fármacos , Acetilcolinesterasa/genética , Animales , Femenino , India , Resistencia a los Insecticidas/genética , Mutación , Piretrinas/síntesis química , Rhipicephalus/enzimología , Rhipicephalus/genética , Canales de Sodio/genética
14.
Bioorg Med Chem Lett ; 27(20): 4643-4646, 2017 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-28927767

RESUMEN

In this communication we report a serendipitously discovered hybrid molecule 1, combining fragment of 3 (an in vivo active antileishmanial molecule) with H2S donor moiety (known for bimodal behavior of cytoprotection and apoptosis), as antileishmanial agent. Compound 1 suppresses 99.82% parasitemia of L. donovani infected macrophages at 12.5µg/ml without even deforming them (CC50>100µg/ml). This compound appears cytotoxic for intracellular amastigotes while cytoprotective to host macrophages. The concept can be utilized to develop high therapeutic index NCE (New Chemical Entities) for other macrophage mediated diseases like tuberculosis and cancer.


Asunto(s)
Antiprotozoarios/química , Indoles/química , Antiprotozoarios/farmacología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Sulfuro de Hidrógeno/metabolismo , Indoles/farmacología , Leishmania donovani/efectos de los fármacos , Macrófagos/citología , Macrófagos/metabolismo , Macrófagos/parasitología
15.
Org Biomol Chem ; 15(15): 3337-3352, 2017 Apr 11.
Artículo en Inglés | MEDLINE | ID: mdl-28368065

RESUMEN

Leishmaniasis, caused by the protozoan parasites of the genus Leishmania, is one of the most neglected diseases endemic in many continents posing enormous global health threats and therefore the discovery of new antileishmanial compounds is of utmost urgency. The antileishmanial activities of a library of sugar amino acid-based linear lipopeptide analogues were examined with the aim to identify potential drug candidates to treat visceral leishmaniasis. It was found that among the synthesized analogues, most of the permethylated compounds exhibited more activity in in vitro studies against intra-macrophagic amastigotes than the non-methylated analogues. SAR and NMR studies revealed that introduction of the N-methyl groups inhibited the formation of any turn structure in these molecules, which led to their improved activities.


Asunto(s)
Aminoácidos/química , Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Lipopéptidos/síntesis química , Lipopéptidos/farmacología , Antiprotozoarios/química , Técnicas de Química Sintética , Diseño de Fármacos , Leishmania donovani/efectos de los fármacos , Lipopéptidos/química , Metilación , Conformación Molecular , Simulación de Dinámica Molecular , Relación Estructura-Actividad
17.
Bull Environ Contam Toxicol ; 96(1): 130-6, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26261047

RESUMEN

In the present investigation, persistence of kresoxim-methyl (a broad spectrum strobilurin fungicide) was studied in water. Results revealed that kresoxim-methyl readily form acid metabolite. Therefore, residues of kresoxim-methyl were quantified on the basis of parent molecule alone and sum total of kresoxim-methyl and its acid metabolite. In water, influence of various abiotic factors like pH, temperature, light and atmospheric carbon dioxide level on dissipation of kresoxim-methyl was studied. The half life value for kresoxim-methyl and total residue varied from 1 to 26.1 and 6.1 to 94.0 days under different conditions. Statistical analysis revealed the significant effect of abiotic factors on the dissipation of kresoxim-methyl from water.


Asunto(s)
Fungicidas Industriales/química , Fenilacetatos/química , Contaminantes Químicos del Agua/química , Dióxido de Carbono , Fungicidas Industriales/efectos de la radiación , Semivida , Luz , Metacrilatos/química , Metacrilatos/efectos de la radiación , Fenilacetatos/efectos de la radiación , Estrobilurinas , Temperatura , Agua , Contaminantes Químicos del Agua/efectos de la radiación
18.
J Antimicrob Chemother ; 70(2): 518-27, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25389223

RESUMEN

OBJECTIVES: The objective of this study was to identify a nitroimidazo-oxazole lead molecule for the treatment of visceral leishmaniasis (VL). METHODS: A library of 72 nitroimidazo-oxazoles was evaluated in vitro for their antileishmanial activity against luciferase-transfected DD8 amastigotes of Leishmania donovani. On the basis of their in vitro potency and pharmacokinetic properties, the promising compounds were tested in acute BALB/c mouse and chronic hamster models of VL via oral administration and efficacy was evaluated by microscopic counting of amastigotes after Giemsa staining. The best antileishmanial candidates (racemate DNDI-VL-2001) and its R enantiomer (DNDI-VL-2098) were evaluated in vitro against a range of Leishmania strains. These candidates were further studied in a hamster model using various dose regimens. Cytokine and inducible nitric oxide synthase estimations by real-time PCR and nitric oxide generation by Griess assay were also carried out for DNDI-VL-2098. RESULTS: In vitro screening of nitroimidazo-oxazole compounds identified the racemate DNDI-VL-2001 (6-nitroimidazo-oxazole derivative) and its enantiomers as candidates for further evaluation in in vivo models of VL. DNDI-VL-2098 (IC50 of 0.03 µM for the DD8 strain) showed excellent in vivo activity in both mouse and hamster models, with an ED90 value of 3.7 and <25 mg/kg, respectively, and was also found to be very effective against high-grade infection in the hamster model. Our studies revealed that, along with leishmanicidal activity, DNDI-VL-2098 was also capable of inducing host-protective immune cells to suppress Leishmania parasites in hamsters. CONCLUSIONS: These studies led to the identification of compound DNDI-VL-2098 as a preclinical candidate for further drug development as an oral treatment for VL.


Asunto(s)
Antiprotozoarios/farmacología , Leishmania donovani/efectos de los fármacos , Leishmaniasis Visceral/tratamiento farmacológico , Administración Oral , Animales , Antiprotozoarios/administración & dosificación , Química Farmacéutica , Cricetinae , Citocinas/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Composición de Medicamentos , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Concentración 50 Inhibidora , Leishmaniasis Visceral/metabolismo , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitroimidazoles/administración & dosificación , Nitroimidazoles/farmacología , Pruebas de Sensibilidad Parasitaria , Factores de Tiempo
19.
Bioorg Med Chem Lett ; 25(2): 410-3, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25475205

RESUMEN

Some novel heteroretinoid-bisbenzylidine ketone hybrids have been synthesized and evaluated for their in vitro antileishmanial activity against intramacrophagic amastigotes of Leishmania donovani. Among all the nine synthetic compounds, five compounds (7c, 7d and 7f-h) have shown significant (less than 7µM) activity against intramacrophagic amastigotes. The IC50 values of these compounds were found better than the reference drugs sodium stibogluconate (SSG) and miltefosine. This study helped us in identifying the new class of compounds that could be exploited as potent antileishmanial agents.


Asunto(s)
Antiprotozoarios/síntesis química , Antiprotozoarios/farmacología , Cetonas/síntesis química , Leishmania donovani/efectos de los fármacos , Leishmaniasis/tratamiento farmacológico , Retinoides/química , Animales , Gluconato de Sodio Antimonio/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Chlorocebus aethiops , Concentración 50 Inhibidora , Leishmaniasis/parasitología , Macrófagos/efectos de los fármacos , Macrófagos/parasitología , Ratones , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacología , Relación Estructura-Actividad , Células Vero
20.
Environ Monit Assess ; 187(1): 4076, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25384368

RESUMEN

Persistence behavior of insecticides chlorpyriphos, profenofos, triazophos, cypermethrin, and deltamethrin following the use of three combination formulations Action 505 (chlorpyriphos + cypermethrin), Roket 44EC (profenofos + cypermethrin), and Anaconda Plus (triazophos + deltamethrin) was studied in cabbage following the spray application at the recommended and double doses. Bio-efficacy of these formulations was also evaluated against mustard aphids (Lipaphis erysimi Kaltenbach) and diamondback moth (Plutella xylostella L.). The residues of different insecticides persisted for 5-8 days at low dose and 8-12 days at high dose. The residues dissipated with time and 87-100% dissipation was recorded on the 8th day. The half-life values varied from 0.4 to 1.6 days. Based on the acceptable daily intake (ADI) values, a safe waiting period of 1 day has been suggested for the formulations Action 505 and Roket 44EC and 3 days for Anaconda Plus at the recommended dose of application. Action (1.6 L/ha) treatment was found to be the best as it significantly reduced the diamondback moth (DBM) (~60%) and aphid population (~70%) besides giving the highest yield (170% increase over control).


Asunto(s)
Brassica/química , Monitoreo del Ambiente , Insecticidas/análisis , Residuos de Plaguicidas/análisis , Animales , Áfidos , Semivida , Control de Insectos/métodos , Insecticidas/toxicidad , Mariposas Nocturnas , Residuos de Plaguicidas/toxicidad
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