Antidiabetic potential of Brachylaena discolor

Background: The traditional African herbal medicinal system has many reports of anti-diabetic food plants with no known side effects. Such plants and their products have been widely prescribed for diabetic treatment with little known mechanistic basis of their functioning. Therefore, these natural products need to be evaluated scientifically in order to confirm antidiabetic property claims.Materials and Methods: In this study, leaves of Brachylaena discolor were evaluated for potential to inhibit α-amylase and α-glucosidase. The leaves were also screened for toxicity and free radical scavenging capacity.Results: Results from the study show that the methanolic extract gave a higher α-glucosidase inhibition potential and was able to effectively scavenge free radicals better than the aqueous extract. The toxicity, cytotoxicity and mutagenicity screen also showed that both plant extracts are safe for use.Conclusion: These results therefore indicate that B. discolor has the potential for use as a potential dietary adjunct or therapy for the treatment of diabetes.Key words: Brachylaena discolor, α-amylase, α-glucosidase, DPPH, toxicit

The whole story: treatment outcomes with Symbicort®

AbstractAsthma is a chronic inflammatory disorder of the airways that has a considerable socioeconomic impact. Asthma management guidelines have been introduced to help provide better long-term control of asthma. Although recommended guidelines may increase the direct medication costs, the overall direct costs of asthma may be reduced due to fewer exacerbations. In addition, indirect costs due to lost productivity and mortality are reduced and patients have an improved quality of life. Inhaled corticosteroids are first-line therapy in the treatment of persistent asthma. Against this background, we have assessed the cost-effectiveness of Symbicort® (budesonide and formoterol in a single inhaler), atreatmentthat provides better control of asthma compared with budesonide alone.While the prescribing costs of Symbicort® were found to be higher than for budesonide alone, these were partially offset by reduced costs due to fewer asthma exacerbations and a reduced need for other medications. Combined long-term therapy with budesonide and formoterol also improves patient quality of life compared with budesonide alone. Two other factors associated with asthma treatment success and cost-effectiveness are patient/physician education and good patient adherence to prescribed therapy. The introduction of a single inhaler that is easy to use in simple treatment regimens may improve patient adherence to prescribed medication, thus resulting in improved asthma control and fewer exacerbations.Treatment with Symbicort® is more cost-effective than treatment with budesonide alone

ANTIDIABETIC POTENTIAL OF BRACHYLAENA DISCOLOR

Background: The traditional African herbal medicinal system has many reports of anti-diabetic food plants with no known side effects. Such plants and their products have been widely prescribed for diabetic treatment with little known mechanistic basis of their functioning. Therefore, these natural products need to be evaluated scientifically in order to confirm antidiabetic property claims. Materials and Methods: In this study, leaves of Brachylaena discolor were evaluated for potential to inhibit α-amylase and α-glucosidase. The leaves were also screened for toxicity and free radical scavenging capacity. Results: Results from the study show that the methanolic extract gave a higher α-glucosidase inhibition potential and was able to effectively scavenge free radicals better than the aqueous extract. The toxicity, cytotoxicity and mutagenicity screen also showed that both plant extracts are safe for use. Conclusion: These results therefore indicate that B. discolor has the potential for use as a potential dietary adjunct or therapy for the treatment of diabetes

MAGI-1 Modulates AMPA Receptor Synaptic Localization and Behavioral Plasticity in Response to Prior Experience

It is well established that the efficacy of synaptic connections can be rapidly modified by neural activity, yet how the environment and prior experience modulate such synaptic and behavioral plasticity is only beginning to be understood. Here we show in C. elegans that the broadly conserved scaffolding molecule MAGI-1 is required for the plasticity observed in a glutamatergic circuit. This mechanosensory circuit mediates reversals in locomotion in response to touch stimulation, and the AMPA-type receptor (AMPAR) subunits GLR-1 and GLR-2, which are required for reversal behavior, are localized to ventral cord synapses in this circuit. We find that animals modulate GLR-1 and GLR-2 localization in response to prior mechanosensory stimulation; a specific isoform of MAGI-1 (MAGI-1L) is critical for this modulation. We show that MAGI-1L interacts with AMPARs through the intracellular domain of the GLR-2 subunit, which is required for the modulation of AMPAR synaptic localization by mechanical stimulation. In addition, mutations that prevent the ubiquitination of GLR-1 prevent the decrease in AMPAR localization observed in previously stimulated magi-1 mutants. Finally, we find that previously-stimulated animals later habituate to subsequent mechanostimulation more rapidly compared to animals initially reared without mechanical stimulation; MAGI-1L, GLR-1, and GLR-2 are required for this change in habituation kinetics. Our findings demonstrate that prior experience can cause long-term alterations in both behavioral plasticity and AMPAR localization at synapses in an intact animal, and indicate a new, direct role for MAGI/S-SCAM proteins in modulating AMPAR localization and function in the wake of variable sensory experience

UEV-1 Is an Ubiquitin-Conjugating Enzyme Variant That Regulates Glutamate Receptor Trafficking in C. elegans Neurons

The regulation of AMPA-type glutamate receptor (AMPAR) membrane trafficking is a key mechanism by which neurons regulate synaptic strength and plasticity. AMPAR trafficking is modulated through a combination of receptor phosphorylation, ubiquitination, endocytosis, and recycling, yet the factors that mediate these processes are just beginning to be uncovered. Here we identify the ubiquitin-conjugating enzyme variant UEV-1 as a regulator of AMPAR trafficking in vivo. We identified mutations in uev-1 in a genetic screen for mutants with altered trafficking of the AMPAR subunit GLR-1 in C. elegans interneurons. Loss of uev-1 activity results in the accumulation of GLR-1 in elongated accretions in neuron cell bodies and along the ventral cord neurites. Mutants also have a corresponding behavioral defect—a decrease in spontaneous reversals in locomotion—consistent with diminished GLR-1 function. The localization of other synaptic proteins in uev-1-mutant interneurons appears normal, indicating that the GLR-1 trafficking defects are not due to gross deficiencies in synapse formation or overall protein trafficking. We provide evidence that GLR-1 accumulates at RAB-10-containing endosomes in uev-1 mutants, and that receptors arrive at these endosomes independent of clathrin-mediated endocytosis. UEV-1 homologs in other species bind to the ubiquitin-conjugating enzyme Ubc13 to create K63-linked polyubiquitin chains on substrate proteins. We find that whereas UEV-1 can interact with C. elegans UBC-13, global levels of K63-linked ubiquitination throughout nematodes appear to be unaffected in uev-1 mutants, even though UEV-1 is broadly expressed in most tissues. Nevertheless, ubc-13 mutants are similar in phenotype to uev-1 mutants, suggesting that the two proteins do work together to regulate GLR-1 trafficking. Our results suggest that UEV-1 could regulate a small subset of K63-linked ubiquitination events in nematodes, at least one of which is critical in regulating GLR-1 trafficking

Nociceptors: a phylogenetic view

The ability to react to environmental change is crucial for the survival of an organism and an essential prerequisite is the capacity to detect and respond to aversive stimuli. The importance of having an inbuilt “detect and protect” system is illustrated by the fact that most animals have dedicated sensory afferents which respond to noxious stimuli called nociceptors. Should injury occur there is often sensitization, whereby increased nociceptor sensitivity and/or plasticity of nociceptor-related neural circuits acts as a protection mechanism for the afflicted body part. Studying nociception and nociceptors in different model organisms has demonstrated that there are similarities from invertebrates right through to humans. The development of technology to genetically manipulate organisms, especially mice, has led to an understanding of some of the key molecular players in nociceptor function. This review will focus on what is known about nociceptors throughout the Animalia kingdom and what similarities exist across phyla; especially at the molecular level of ion channels

Using C. elegans to decipher the cellular and molecular mechanisms underlying neurodevelopmental disorders

Prova tipográfica (uncorrected proof)Neurodevelopmental disorders such as epilepsy, intellectual disability (ID), and autism spectrum disorders (ASDs) occur in over 2 % of the population, as the result of genetic mutations, environmental factors, or combination of both. In the last years, use of large-scale genomic techniques allowed important advances in the identification of genes/loci associated with these disorders. Nevertheless, following association of novel genes with a given disease, interpretation of findings is often difficult due to lack of information on gene function and effect of a given mutation in the corresponding protein. This brings the need to validate genetic associations from a functional perspective in model systems in a relatively fast but effective manner. In this context, the small nematode, Caenorhabditis elegans, presents a good compromise between the simplicity of cell models and the complexity of rodent nervous systems. In this article, we review the features that make C. elegans a good model for the study of neurodevelopmental diseases. We discuss its nervous system architecture and function as well as the molecular basis of behaviors that seem important in the context of different neurodevelopmental disorders. We review methodologies used to assess memory, learning, and social behavior as well as susceptibility to seizures in this organism. We will also discuss technological progresses applied in C. elegans neurobiology research, such as use of microfluidics and optogenetic tools. Finally, we will present some interesting examples of the functional analysis of genes associated with human neurodevelopmental disorders and how we can move from genes to therapies using this simple model organism.The authors would like to acknowledge Fundação para a Ciência e Tecnologia (FCT) (PTDC/SAU-GMG/112577/2009). AJR and CB are recipients of FCT fellowships: SFRH/BPD/33611/2009 and SFRH/BPD/74452/2010, respectively

High gamma oscillations in medial temporal lobe during overt production of speech and gestures

The study of the production of co-speech gestures (CSGs), i.e., meaningful hand movements that often accompany speech during everyday discourse, provides an important opportunity to investigate the integration of language, action, and memory because of the semantic overlap between gesture movements and speech content. Behavioral studies of CSGs and speech suggest that they have a common base in memory and predict that overt production of both speech and CSGs would be preceded by neural activity related to memory processes. However, to date the neural correlates and timing of CSG production are still largely unknown. In the current study, we addressed these questions with magnetoencephalography and a semantic association paradigm in which participants overtly produced speech or gesture responses that were either meaningfully related to a stimulus or not. Using spectral and beamforming analyses to investigate the neural activity preceding the responses, we found a desynchronization in the beta band (15-25 Hz), which originated 900 ms prior to the onset of speech and was localized to motor and somatosensory regions in the cortex and cerebellum, as well as right inferior frontal gyrus. Beta desynchronization is often seen as an indicator of motor processing and thus reflects motor activity related to the hand movements that gestures add to speech. Furthermore, our results show oscillations in the high gamma band (50-90 Hz), which originated 400 ms prior to speech onset and were localized to the left medial temporal lobe. High gamma oscillations have previously been found to be involved in memory processes and we thus interpret them to be related to contextual association of semantic information in memory. The results of our study show that high gamma oscillations in medial temporal cortex play an important role in the binding of information in human memory during speech and CSG production

Neuronal Toxicity in Caenorhabditis elegans from an Editing Site Mutant in Glutamate Receptor Channels

Ionotropic glutamate receptors (iGluRs) in Caenorhabditis elegans are predicted to have high permeability for Ca2+ because of glutamine (Q) residues in the pore loop. This contrasts to the low Ca2+ permeability of similar iGluRs in principal neurons of mammals, because of an edited arginine (R) at the critical pore position in at least one channel subunit. Here, we introduced the R residue into the pore loop of a glutamate receptor subunit, GLR−2, in C. elegans. GLR−2(R) participated in channel formation, as revealed by decreased rectification of kainate−evoked currents in electrophysiological recordings when GLR−2(R) and the wild−type GLR−2(Q) were coexpressed in worms. Notably, the transgenic worms exhibited, at low penetrance, strong phenotypic impairments including uncoordination, neuronal degeneration, developmental arrest, and lethality. Penetrance of adverse phenotypes could be enhanced by transgenic expression of an optimal GLR−2(Q)/(R) ratio, implicating channel activity as the cause. In direct support, a mutation in eat−4, which prevents glutamatergic transmission, suppressed adverse phenotypes. Suppression was also achieved by mutation in calreticulin, which is necessary for maintainance of intracellular Ca2+ stores in the endoplasmic reticulum. Thus, synaptically activated GLR−2(R)−containing iGluR channels appear to trigger inappropriate, neurotoxic Ca2+ release from intracellular stores