RESUMEN
The binding of heat stable enterotoxin (STa) secreted by enterotoxigenic Escherichia coli (ETEC) to the extracellular domain of guanylyl cyclase c (ECDGC-C) causes activation of a signaling cascade, which ultimately results in watery diarrhea. We carried out this study with the objective of finding ligands that would interfere with the binding of STa on ECDGC-C. With this view in mind, we tested the biological activity of a alkaloid rich fraction of Holarrhena pubescens against ETEC under in vitro conditions. Since this fraction showed significant antibacterial activity against ETEC, we decided to test the screen binding affinity of nine compounds of steroidal alkaloid type from Holarrhena pubescens against extracellular domain (ECD) by molecular docking and identified three compounds with significant binding energy. Molecular dynamics simulations were performed for all the three lead compounds to establish the stability of their interaction with the target protein. Pharmacokinetics and toxicity profiling of these leads demonstrated that they possessed good drug-like properties. Furthermore, the ability of these leads to inhibit the binding of STa to ECD was evaluated. This was first done by identifying amino acid residues of ECDGC-C binding to STa by protein-protein docking. The results were matched with our molecular docking results. We report here that holadysenterine, one of the lead compounds that showed a strong affinity for the amino acid residues on ECDGC-C, also binds to STa. This suggests that holadysenterine has the potential to inhibit binding of STa on ECD and can be considered for future study, involving its validation through in vitro assays and animal model studies.
Asunto(s)
Toxinas Bacterianas/metabolismo , Enterotoxinas/metabolismo , Proteínas de Escherichia coli/metabolismo , Holarrhena/metabolismo , Receptores de Enterotoxina/metabolismo , Alcaloides/metabolismo , Antidiarreicos/farmacología , Sitios de Unión , Simulación por Computador , Diarrea/tratamiento farmacológico , Escherichia coli Enterotoxigénica/metabolismo , Enterotoxinas/fisiología , Proteínas de Escherichia coli/fisiología , Guanilato Ciclasa/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Corteza de la Planta/metabolismo , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacosRESUMEN
Various abiotic stressors like drought, salinity, temperature, and heavy metals are major environmental stresses that affect agricultural productivity and crop yields all over the world. Continuous changes in climatic conditions put selective pressure on the microbial ecosystem to produce exopolysaccharides. Apart from soil aggregation, exopolysaccharide (EPS) production also helps in increasing water permeability, nutrient uptake by roots, soil stability, soil fertility, plant biomass, chlorophyll content, root and shoot length, and surface area of leaves while also helping maintain metabolic and physiological activities during drought stress. EPS-producing microbes can impart salt tolerance to plants by binding to sodium ions in the soil and preventing these ions from reaching the stem, thereby decreasing sodium absorption from the soil and increasing nutrient uptake by the roots. Biofilm formation in high-salinity soils increases cell viability, enhances soil fertility, and promotes plant growth and development. The third environmental stressor is presence of heavy metals in the soil due to improper industrial waste disposal practices that are toxic for plants. EPS production by soil bacteria can result in the biomineralization of metal ions, thereby imparting metal stress tolerance to plants. Finally, high temperatures can also affect agricultural productivity by decreasing plant metabolism, seedling growth, and seed germination. The present review discusses the role of exopolysaccharide-producing plant growth-promoting bacteria in modulating plant growth and development in plants and alleviating extreme abiotic stress condition. The review suggests exploring the potential of EPS-producing bacteria for multiple abiotic stress management strategies.
Asunto(s)
Bacterias/metabolismo , Plantas , Polisacáridos Bacterianos/metabolismo , Estrés Fisiológico , Bacterias/clasificación , Biopelículas/crecimiento & desarrollo , Sequías , Metales Pesados/metabolismo , Desarrollo de la Planta , Plantas/metabolismo , Plantas/microbiología , Salinidad , TemperaturaRESUMEN
Alzheimer's disease is a complex neurodegenerative disease affecting millions of individuals worldwide. Earlier it was diagnosed only via clinical assessments and confirmed by postmortem brain histopathology. The development of validated biomarkers for Alzheimer's disease has given impetus to improve diagnostics and accelerate the development of new therapies. Functional imaging like positron emission tomography (PET), single photon emission computed tomography (SPECT), functional magnetic resonance imaging (fMRI), and proton magnetic resonance spectroscopy provides a means of detecting and characterising the regional changes in brain blood flow, metabolism, and receptor binding sites that are associated with Alzheimer's disease. Multimodal neuroimaging techniques have indicated changes in brain structure and metabolic activity, and an array of neurochemical variations that are associated with neurodegenerative diseases. Radiotracer-based PET and SPECT potentially provide sensitive, accurate methods for the early detection of disease. This paper presents a review of neuroimaging modalities like PET, SPECT, and selected imaging biomarkers/tracers used for the early diagnosis of AD. Neuroimaging with such biomarkers and tracers could achieve a much higher diagnostic accuracy for AD and related disorders in the future.
RESUMEN
The mechanisms responsible for cholinergic dysfunction associated learning and memory impairment during hypoxia are not well-understood. However it is known that inflammatory mediators like inducible nitric oxide synthase (iNOS) hamper the functions of cholinergic neurons. In this present experiment we made an effort to study the iNOS expression mediated retrograde and anterograde memory impairment in Balb/c mice following acute hypobaric hypoxia (at an altitude of 23,000ft for 6h) using elevated plus maze and passive avoidance step-through tasks. Our results demonstrated that hypoxia transiently impairs the retrograde memory without affecting the anterograde memory functions, accompanied with a substantial rise in iNOS expression and nitric oxide levels in cerebral cortex on days 2 and 3 post hypoxia. Treatment with aminoguanidine (iNOS inhibitor ), resulted in down-regulation of the iNOS expression, attenuation of the surge of nitric oxide (NO) in cerebral cortex and reversal of retrograde memory impairment due to hypoxia. Moreover the reduced AChE activity and elevated lipid peroxidation in cerebral cortex were evident during post hypoxia re-oxygenation period, which was not observed in the hippocampus. Additionally, NO donor spermine NONOate could inhibit the AChE activity in brain homogenates in a concentration-dependent manner, which further substantiate that nitric oxide produced during post hypoxia re-oxygenation, primarily contributes to the observed inhibition of cortical AChE activity. Based on these experiments we hypothesize that the NO burst as a result of iNOS upregulation during hypoxia interrupts the memory consolidation by altering the cholinergic functions.
Asunto(s)
Acetilcolinesterasa/metabolismo , Hipoxia/enzimología , Hipoxia/psicología , Trastornos de la Memoria/psicología , Óxido Nítrico Sintasa de Tipo II/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Amnesia Anterógrada/inducido químicamente , Amnesia Anterógrada/psicología , Amnesia Retrógrada/inducido químicamente , Amnesia Retrógrada/psicología , Animales , Reacción de Prevención/efectos de los fármacos , Western Blotting , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/enzimología , Inhibidores de la Colinesterasa/farmacología , Inhibidores Enzimáticos/farmacología , Gliceraldehído-3-Fosfato Deshidrogenasas/biosíntesis , Gliceraldehído-3-Fosfato Deshidrogenasas/genética , Guanidinas/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/enzimología , Aprendizaje/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Trastornos de la Memoria/inducido químicamente , Ratones , Ratones Endogámicos BALB C , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Estrés Oxidativo/efectos de los fármacos , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
INTRODUCTION: Seizures are accompanied by autonomic dysfunction which in turn influences cardiovascular variables. A method for simultaneous acquisition of electroencephalogram (EEG) and arterial blood pressure (BP) during seizures in conscious animals has not previously been described. METHODS: The effect of pentylenetetrazole (PTZ) was first studied on isolated rat atria. EEG and BP were then monitored simultaneously in conscious rats, with a chronically implanted radiotelemetric device. Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and heart rate (HR) during epileptiform seizures induced by intraperitoneal administration of PTZ were monitored to validate the method. RESULTS: PTZ did not have significant inotropic or chronotropic effect in isolated atria. The radiotelemetry system used to acquire data in unrestrained conscious rats enabled us to study neurological excitation (EEG) and cardiovascular variables (BP and HR) during seizures. Our results demonstrated that this method can be used to study the effect of neuronal excitation on cardiovascular variables and vice versa.