Rutin as promising drug for the treatment of Parkinson’s disease: an assessment of MAO-B inhibitory potential by docking,molecular dynamics and DFT studies

ABSTRACT

Inhibitors of monoamine oxidase (MAO)-B have been used for many years in the therapy of Parkinson’s disease (PD). Owing to the safety concerns of the currently used agents, the discovery of novel scaffolds is of considerable interest. MAO-B inhibitory potential of rutin, a flavonoid derived from natural sources, has been established in experimental findings. Hence, the current study seeks to examine the interactions between rutin and crystal structure of human MAO-B enzyme. Molecular docking calculations, as well as molecular dynamics simulations, were employed to investigate the binding mode and the stability of the rutin/MAO-B complex. Energies of highest occupied/lowest unoccupied molecular orbitals were computed through DFT studies and used to calculate electron affinity, hardness, chemical potential, electronegativity, and electrophilicity index in order to investigate the capability of these parameters to influence the ligand–receptor interactions. It was found that rutin traverses both the entrance cavity and the substrate cavity, forcing the Ile-199 ‘gate’ to rotate into its open conformation. It results in the fusion of the two cavities of the MAO-B binding site and directly leads to better binding interactions. Results of the current study can be used for lead modification and development of novel drugs for the treatment of PD.     

Distinct signaling pathways regulate TLR2 co-stimulatory function in human T cells

Toll-like receptor 2 (TLR2) serves as a co-stimulatory receptor for human T cells by enhancing T cell receptor (TCR)-induced cytokine production and proliferation. However, it is unknown where signals from the TCR and TLR2 converge to enhance T cell activation. To address this gap, we examined changes in TCR-induced signaling following concurrent TLR2 activation in human T cells. Both proximal TCR-mediated signaling and early NFκB activation were not enhanced by TCR andTLR2 co-activation, potentially due to the association of TLR2 with TLR10. Instead, TLR2 co-induction did augment Akt and Erk1/Erk2 activation in human T cells. These findings demonstrate that TLR2 activates distinct signaling pathways in human T cells and suggest that alterations in expression of TLR2 co-receptors may contribute to aberrant T cell responses.     

Morningness-eveningness preferences,learning approach and academic achievement of undergraduate medical students

ABSTRACT

Several studies have focused on determining the effect of chronotype and learning approach on academic achievement separately indicating that morning types have an academic advantage over the evening types and so have the deep learners over the surface learners. But, surprisingly none have assessed the possible relationship between chronotype and learning approach. So, the current study aimed to evaluate this association and their individual influence on academic performance as indicated by the Cumulative Grade Point Average (CGPA) as well as the effect of their interaction on academic performance. The study included 345 undergraduate medical students who responded to reduced Morningness-Eveningness Questionnaire and Biggs Revised Two-Factor Study Process Questionnaire. Morning types indulged in deep learning while evening types in surface learning. Morning and evening types did not differ on academic performance but deep learners had better academic outcomes than their counterparts. The interaction between chronotype and learning approach was significant on determining academic achievement. Our findings gave the impression that chronotype could have an impact on academic performance not directly but indirectly through learning approaches.     

Normalization of miRNA qPCR high-throughput data: a comparison of methods

Low-density quantitative real-time PCR (qPCR) arrays are often used to profile expression patterns of microRNAs in various biological milieus. To achieve accurate analysis of expression of miRNAs, non-biological sources of variation in data should be removed through precise normalization of data. We have systematically compared the performance of 19 normalization methods on different subsets of a real miRNA qPCR dataset that covers 40 human tissues. After robustly modeling the mean squared error (MSE) in normalized data, we demonstrate lower variability between replicates is achieved using various methods not applied to high-throughput miRNA qPCR data yet. Normalization methods that use splines or wavelets smoothing to estimate and remove Cq dependent non-linearity between pairs of samples best reduced the MSE of differences in Cq values of replicate samples. These methods also retained between-group variability in different subsets of the dataset.     

Astrocyte- neuron interaction as a mechanism responsible for generation of neural synchrony: a study based on modeling and experiments

Neural synchronization is considered as an important mechanism for information processing. In addition, based on recent neurophysiologic findings, it is believed that astrocytes regulate the synaptic transmission of neuronal networks. Therefore, the present study focused on determining the functional contribution of astrocytes in neuronal synchrony using both computer simulations and extracellular field potential recordings. For computer simulations, as a first step, a minimal network model is constructed by connecting two Morris-Lecar neuronal models. In this minimal model, astrocyte-neuron interactions are considered in a functional-based procedure. Next, the minimal network is extended and a biologically plausible neuronal population model is developed which considers functional outcome of astrocyte-neuron interactions too. The employed structure is based on the physiological and anatomical network properties of the hippocampal CA1 area. Utilizing these two different levels of modeling, it is demonstrated that astrocytes are able to change the threshold value of transition from synchronous to asynchronous behavior among neurons. In this way, variations in the interaction between astrocytes and neurons lead to the emergence of synchronous/asynchronous patterns in neural responses. Furthermore, population spikes are recorded from CA1 pyramidal neurons in rat hippocampal slices to validate the modeling results. It demonstrates that astrocytes play a primary role in neuronal firing synchronicity and synaptic coordination. These results may offer a new insight into understanding the mechanism by which astrocytes contribute to stabilizing neural activities.     

Supplementation with α-Lipoic Acid,CoQ10, and Vitamin E Augments Running Performance and Mitochondrial Function in Female Mice

Antioxidant supplements are widely consumed by the general public; however, their effects of on exercise performance are controversial. The aim of this study was to examine the effects of an antioxidant cocktail (α-lipoic acid, vitamin E and coenzyme Q10) on exercise performance, muscle function and training adaptations in mice. C57Bl/J6 mice were placed on antioxidant supplement or placebo-control diets (n = 36/group) and divided into trained (8 wks treadmill running) (n = 12/group) and untrained groups (n = 24/group). Antioxidant supplementation had no effect on the running performance of trained mice nor did it affect training adaptations; however, untrained female mice that received antioxidants performed significantly better than placebo-control mice (p ≤ 0.05). Furthermore, antioxidant-supplemented females (untrained) showed elevated respiratory capacity in freshly excised muscle fibers (quadriceps femoris) (p ≤ 0.05), reduced oxidative damage to muscle proteins (p ≤ 0.05), and increased expression of mitochondrial proteins (p ≤ 0.05) compared to placebo-controls. These changes were attributed to increased expression of proliferator-activated receptor gamma coactivator 1α (PGC-1α) (p ≤ 0.05) via activation of AMP-activated protein kinase (AMPK) (p ≤ 0.05) by antioxidant supplementation. Overall, these results indicate that this antioxidant supplement exerts gender specific effects; augmenting performance and mitochondrial function in untrained females, but does not attenuate training adaptations.     

Transition from Diffusion‐Controlled Intercalation into Extrinsically Pseudocapacitive Charge Storage of MoS2 by Nanoscale Heterostructuring

2D nanomaterials have been found to show surface‐dominant phenomena and understanding this behavior is crucial for establishing a relationship between a material's structure and its properties. Here, the transition of molybdenum disulfide (MoS₂) from a diffusion‐controlled intercalation to an emergent surface redox capacitive behavior is demonstrated. The ultrafast pseudocapacitive behavior of MoS₂ becomes more prominent when the layered MoS₂ is downscaled into nanometric sheets and hybridized with reduced graphene oxide (RGO). This extrinsic behavior of the 2D hybrid is promoted by the fast Faradaic charge‐transfer kinetics at the interface. The heterostructure of the 2D hybrid, as observed via high‐angle annular dark field–scanning transmission electron microscopy and Raman mapping, with a 1T MoS₂ phase at the interface and a 2H phase in the bulk is associated with the synergizing capacitive performance. This 1T phase is stabilized by the interactions with the RGO. These results provide fundamental insights into the surface effects of 2D hetero‐nanosheets on emergent electrochemical properties.