Binding and antioxidant properties of therapeutically important plant flavonoids in biomembranes: insights from spectroscopic and quantum chemical studies

Plant flavonoids are emerging as novel therapeutic drugs for free radical mediated diseases, for which cell membranes mainly serve as targets for lipid peroxidation and related deleterious effects. Screening and characterization of these ubiquitous, therapeutically potent polyphenolic compounds require a clear understanding regarding their binding and possible locations in membranes, as well as quantitative estimates of relevant parameters such as partition coefficients, antioxidant and radical scavenging capacities. In this article we present perspectives emphasizing novel uses of the exquisitely sensitive 'two color' intrinsic fluorescence of plant flavonoids (which arise due to highly efficient photoinduced excited state intramolecular proton transfer (ESIPT) reactions) to explore their binding to model biomembranes consisting of phosphatidylcholine liposomes. Extension of such studies to natural biomembranes of relevant interest is also exemplified. Spectrophotometric assays reveal that typical mono- as well as poly-hydroxy substituted flavonoids have remarkable inhibitory actions on lipid peroxidation, and are significantly more potent antioxidants (2.5-4 times higher) compared to the reference compound Trolox (an water soluble derivative of vitamin E). The structure-activity relationships emerging from such studies are consistent with theoretical predictions based on quantum chemical computations.     

Modeling and experimental analyses reveals signaling plasticity in a bi-modular assembly of CD40 receptor activated kinases

Depending on the strength of signal dose, CD40 receptor (CD40) controls ERK-1/2 and p38MAPK activation. At low signal dose, ERK-1/2 is maximally phosphorylated but p38MAPK is minimally phosphorylated; as the signal dose increases, ERK-1/2 phosphorylation is reduced whereas p38MAPK phosphorylation is reciprocally enhanced. The mechanism of reciprocal activation of these two MAPKs remains un-elucidated. Here, our computational model, coupled to experimental perturbations, shows that the observed reciprocity is a system-level behavior of an assembly of kinases arranged in two modules. Experimental perturbations with kinase inhibitors suggest that a minimum of two trans-modular negative feedback loops are required to reproduce the experimentally observed reciprocity. The bi-modular architecture of the signaling pathways endows the system with an inherent plasticity which is further expressed in the skewing of the CD40-induced productions of IL-10 and IL-12, the respective anti-inflammatory and pro-inflammatory cytokines. Targeting the plasticity of CD40 signaling significantly reduces Leishmania major infection in a susceptible mouse strain. Thus, for the first time, using CD40 signaling as a model, we show how a bi-modular assembly of kinases imposes reciprocity to a receptor signaling. The findings unravel that the signalling plasticity is inherent to a reciprocal system and that the principle can be used for designing a therapy.     

Accelerated exchange of exon segments in Viperid three-finger toxin genes (<Emphasis Type="Italic">Sistrurus catenatus edwardsii</Emphasis>; Desert Massasauga)

Background  

Snake venoms consist primarily of proteins and peptides showing a myriad of potent biological activities which have been shaped by both adaptive and neutral selective forces. Venom proteins are encoded by multigene families that have evolved through a process of gene duplication followed by accelerated evolution in the protein coding region.     

Prospect of Bioflavonoid Fisetin as a Quadruplex DNA Ligand: A Biophysical Approach

Quadruplex (G₄) forming sequences in telomeric DNA and c-myc promoter regions of human DNA are associated with tumorogenesis. Ligands that can facilitate or stabilize the formation and increase the stabilization of G₄ can prevent tumor cell proliferation and have been regarded as potential anti-cancer drugs. In the present study, steady state and time-resolved fluorescence measurements provide important structural and dynamical insights into the free and bound states of the therapeutically potent plant flavonoid fisetin (3,3′,4′,7-tetrahydroxyflavone) in a G₄ DNA matrix. The excited state intra-molecular proton transfer (ESPT) of fisetin plays an important role in observing and understanding the binding of fisetin with the G₄ DNA. Differential absorption spectra, thermal melting, and circular dichroism spectroscopic studies provide evidences for the formation of G₄ DNA and size exclusion chromatography (SEC) proves the binding and 1∶1 stoichiometry of fisetin in the DNA matrix. Comparative analysis of binding in the presence of EtBr proves that fisetin favors binding at the face of the G-quartet, mostly along the diagonal loop. Time resolved fluorescence anisotropy decay analysis indicates the increase in the restrictions in motion from the free to bound fisetin. We have also investigated the fingerprints of the binding of fisetin in the antiparallel quadruplex using Raman spectroscopy. Preliminary results indicate fisetin to be a prospective candidate as a G₄ ligand.     

Characterization of the structures and dynamics of phosphoric acid doped benzimidazole mixtures: a molecular dynamics study

Benzimidazole-based polymer membranes like poly(2,5-benzimidazole) (ABPBI) doped with phosphoric acid (PA) are electrolytes that exhibit high proton conductivity in fuel cells at elevated temperatures. The benzimidazole (BI) moiety is an important constituent of these membranes, so the present work was performed in order to achieve a molecular understanding of the BI–PA interactions in the presence of varying levels of the PA dopant, using classical molecular dynamics (MD) simulations. The various hydrogen-bonding interactions, as characterized based on structural properties and hydrogen-bond lifetime calculations, show that both BI and PA molecules exhibit dual proton-acceptor/donor functionality. An examination of diffusion coefficients showed that the diffusion of BI decreases with increasing PA uptake, whereas the diffusion of PA slightly increases. The hydrogen-bond lifetime calculations pointed to the existence of competitive hydrogen bonding between various sites in BI and PA.

Molecular dynamics analysis of the transient temperature increase at void locations in shocked materials: RDX and Cu

Molecular dynamics (MD) simulations of high velocity impact (1–6 km/s) of RDX crystal with a nanometer-sized void, has been carried out to understand the mechanism of increase in temperature at void locations under shock loading. Similar simulations are then carried out on single-crystal copper for better interpretation of the results. A reactive potential that can simulate chemical reactions (ReaxFF) has been used for RDX, whereas an EAM potential has been used for Cu. Increased temperature at the void locations are observed under shock loading. The atomic motion, temperature, average potential energy per atom (PE), and average kinetic energy per atom (KE) in and around the voids are closely monitored in order to understand the reason for temperature increase. We compare our results with existing proposed mechanisms and show that some of the proposed mechanisms are not necessary for increased temperature at a void location. It is shown that the directed particle velocity is efficiently is converted into randomized velocity due to the presence of voids thereby increasing the local temperature transiently. In this initial stage (few picoseconds) of the shock, chemical reactions of energetic materials do not play a part in the temperature rise.     

Effect of adrenalin and acetylcholine on the hypothalamic neurosecretory system in the garden lizard, Calotes versicolor.

Injection of adrenalin or acetylcholine led to enhanced elaboration and release of neurosecretory materials (hyperactivity) in the hypothalamic neurosecretory system of the garden lizard. The hyperactivity apparently came down to the control level of activity at the 120 h stage of the experiment.     

Significant sex difference in the association between C‐reactive protein concentration and anthropometry among 13‐ to 19‐year olds,but not 6‐ to 12‐year olds in Nepal

Life history theory predicts a trade‐off between immunostimulation and growth. Using a cross‐sectional study design, this study aims to test the hypothesis that C‐reactive protein (CRP) is negatively associated with height‐for‐age z‐scores (HAZ scores) and BMI‐for‐age z‐scores (BAZ scores) among 6‐ to 19‐year olds (N = 426) residing in five Nepalese communities. Dried blood spot (DBS) samples were collected and assayed for CRP using an in‐house enzyme immunoassay (EIA). Sex‐ and age‐group‐specific CRP quartiles were used to examine its association with growth in linear mixed‐effects (LME) models. A significant difference was found in the proportion of elevated CRP (>2 mg/L, equivalent to ～3.2 mg/L serum CRP) between 13‐ and 19‐year‐old boys (12%) and girls (4%). Concentrations of CRP were positively associated with HAZ score among adolescent (13–19 years) boys, which may indicate that individuals with greater energy resources have better growth and a better response to infections, thus eliminating the expected trade‐off between body maintenance (immunostimulation) and growth. Adolescent boys with low BAZ and HAZ scores had low CRP values, suggesting that those who do not have enough energy for growth cannot increase their CRP level even when infected with pathogens. Among adolescent girls a positive association was observed between CRP and BAZ scores suggesting the possible effects of chronic low‐grade inflammation due to body fat rather than infection. The association between CRP and growth was less evident among children (6–12 years) compared with adolescents, indicating that the elevated energy requirement needed for the adolescent growth spurt and puberty may play some role. Am J Phys Anthropol 154:42–51, 2014. © 2014 Wiley Periodicals, Inc.     

Nesting Behaviour of the Giant Honeybees <Emphasis Type="Italic">Apis</Emphasis><Emphasis Type="Italic">dorsata</Emphasis> Occurring in Jhargram,West Bengal,India

The giant honeybees Apis dorsata are habituated to construct combs in trees, houses, caves as well as in overhead water reservoir occurring in their nesting localities. To verify their preference for nesting sites if any, surveys were conducted in recent years (2013–16), during nesting seasons of these bees in Jhargram area of West Bengal, India. It is revealed that A. dorsata construct their combs in big, tall, aged simul (Bombax ceiba), bot (Ficus benghalensis) trees mostly, irrespective of localities. Also they were seen to construct nest at the underside of the overhead water reservoir ignoring nesting potential trees occurring nearby. Of course, nesting in the houses, and on the walls of culvert is not uncommon. As the bees constructed more than 100–200 nests at the same nesting site e.g., a tree or/and an overhead water reservoir, depending upon the availability of space for construction of nest it is concluded that these insects prefer colonial nesting.