Visible light-induced cytotoxicity of a dinuclear iron(III) complex of curcumin with low-micromolar IC50 value in cancer cells

Photoactive metal complexes have emerged as potential candidates in the photodynamic therapy (PDT) of cancer. We present here the synthesis, characterization and visible light-triggered anticancer activity of two novel mixed-ligand oxo-bridged iron(III) complexes, viz., {Fe(L)(acac)}(2)(mu-O)](ClO4)(2) (1) and {Fe (L)(cur)}(2)(mu-O)](ClO4)(2) (2) where L is bis-(2-pyridylmethyl)-benzylamine, acac is acetylacetonate and cur is the monoanion of curcumin (bis(4-hydroxy-3-methoxyphenyl)-1,6-diene-3,5-dione). The crystal structure of complex 1 (as PF6 salt, 1a) shows distorted octahedral geometry of each iron(III) centre formed by the FeN3O3 core. The 1: 2 electrolytic complexes are stable in solution and retain their oxo-bridged identity in aqueous medium. Complex 2 has a strong absorption band in the visible region and shows promising photocytotoxicity in HeLa and MCF-7 cancer cells in visible light giving respective IC50 values of 3.1 +/- 0.4 lM and 4.9 +/- 0.5 lM while remains non-toxic in the dark (IC50 > 50 lM). The control complex 1 is inactive both in the light and dark. Complex 2 accumulates in cytoplasm of HeLa and MCF-7 cells as evidenced from fluorescence microscopy and triggers apoptotic cell death via light-assisted generation of reactive oxygen species (ROS). Taken together, complex 2 with its promising photocytotoxicity but negligible dark toxicity in cancer cells has significant photochemotherapeutic potential for applications in PDT. (C) 2015 Elsevier B.V. All rights reserved.

Ac2PIM-responsive miR-150 and miR-143 Target Receptor-interacting Protein Kinase 2 and Transforming Growth Factor Beta-activated Kinase 1 to Suppress NOD2-induced Immunomodulators

Specific and coordinated regulation of innate immune receptor-driven signaling networks often determines the net outcome of the immune responses. Here, we investigated the cross-regulation of toll-like receptor (TLR)2 and nucleotide-binding oligomerization domain (NOD)2 pathways mediated by Ac2PIM, a tetra-acylated form of mycobacterial cell wall component and muramyl dipeptide (MDP), a peptidoglycan derivative respectively. While Ac2PIM treatment of macrophages compromised their ability to induce NOD2-dependent immunomodulators like cyclooxygenase (COX)-2, suppressor of cytokine signaling (SOCS)-3, and matrix metalloproteinase (MMP)-9, no change in the NOD2-responsive NO, TNF-alpha, VEGF-A, and IL-12 levels was observed. Further, genome-wide microRNA expression profiling identified Ac2PIM-responsive miR-150 and miR-143 to target NOD2 signaling adaptors, RIP2 and TAK1, respectively. Interestingly, Ac2PIM was found to activate the SRC-FAK-PYK2-CREB cascade via TLR2 to recruit CBP/P300 at the promoters of miR-150 and miR-143 and epigenetically induce their expression. Loss-of-function studies utilizing specific miRNA inhibitors establish that Ac2PIM, via the miRNAs, abrogate NOD2-induced PI3K-PKC delta-MAPK pathway to suppress beta-catenin-mediated expression of COX-2, SOCS-3, and MMP-9. Our investigation has thus underscored the negative regulatory role of Ac2PIM-TLR2 signaling on NOD2 pathway which could broaden our understanding on vaccine potential or adjuvant utilities of Ac2PIM and/or MDP.

Definition of a serum marker panel for glioblastoma discrimination and identification of Interleukin 1 beta in the microglial secretome as a novel mediator of endothelial cell survival induced by C-reactive protein

Glioblastoma (GBM) is the most common malignant adult primary brain tumor. We profiled 724 cancer-associated proteins in sera of healthy individuals (n = 27) and GBM (n = 28) using antibody microarray. While 69 proteins exhibited differential abundance in GBM sera, a three-marker panel (LYAM1, BHE40 and CRP) could discriminate GBM sera from that of healthy donors with an accuracy of 89.7% and p < 0.0001. The high abundance of C-reactive protein (CRP) in GBM sera was confirmed in 264 independent samples. High levels of CRP protein was seen in GBM but without a change in transcript levels suggesting a non-tumoral origin. Glioma-secreted Interleukin 6 (IL6) was found to induce hepatocytes to secrete CRP, involving JAK-STAT pathway. The culture supernatant from CRP-treated microglial cells induced endothelial cell survival under nutrient-deprivation condition involving CRP-Fc gamma RIII signaling cascade. Transcript profiling of CRP-treated microglial cells identified Interleukin 1 beta (IL1 beta) present in the microglial secretome as the key mediator of CRP-induced endothelial cell survival. IL1 beta neutralization by antibody-binding or siRNA-mediated silencing in microglial cells reduced the ability of the supernatant from CRP-treated microglial cells to induce endothelial cell survival. Thus our study identifies a serum based three-marker panel for GBM diagnosis and provides leads for developing targeted therapies. Biological significance A complex antibody microarray based serum marker profiling identified a three-marker panel - LYAM1, BHE40 and CRP as an accurate discriminator of glioblastoma sera from that of healthy individuals. CRP protein is seen in high levels without a concomitant increase of CRP transcripts in glioblastoma. Glioma-secreted IL6 induced hepatocytes to produce CRP in a JAK-STAT signaling dependent manner. CRP induced microglial cells to release IL1 beta which in turn promoted endothelial cell survival. This study, besides defining a serum panel for glioblastoma discrimination, identified IL1 beta as a potential candidate for developing targeted therapy. (C) 2015 Elsevier B.V. All rights reserved.

Epigenetics and miRNA during bacteria-induced host immune responses

Various cellular processes including the pathogen-specific immune responses, host-pathogen interactions and the related evasion mechanisms rely on the ability of the immune cells to be reprogrammed accurately and in many cases instantaneously. In this context, the exact functions of epigenetic and miRNA-mediated regulation of genes, coupled with recent advent in techniques that aid such studies, make it an attractive field for research. Here, we review examples that involve the epigenetic and miRNA control of the host immune system during infection with bacteria. Interestingly, many pathogens utilize the epigenetic and miRNA machinery to modify and evade the host immune responses. Thus, we believe that global epigenetic and miRNA mapping of such host-pathogen interactions would provide key insights into their cellular functions and help to identify various determinants for therapeutic value.

Light Induced Metastable State of Silver Nitroprusside Probed by Raman Spectroscopy

Low temperature Raman spectroscopic measurements on silver nitroprusside (AgNP), Ag-2Fe(CN)(5)NO] powders display reversible features of a partially converted metastable state. The results are compared with similarly observed metastable state in case of sodium nitroprusside (NaNP) and the differences have been discussed in terms of possible resistance to metastable state formation offered by silver atoms on the basis of hard soft acid base (HSAB) theory.

Sonic hedgehog-responsive lipoxygenases and cyclooxygenase-2 modulate Dectin-1-induced inflammatory cytokines

Immune responses during fungal infections are predominately mediated by 5/15-lipoxygenases (LO)-or cyclooxygenase (COX)-2-catalysed bioactive eicosanoid metabolites like leukotrienes, lipoxins and prostaglandins. Although few host mediators of fungi-triggered eicosanoid production have been established, the molecular mechanism of expression and regulation of 5-LO, 15-LO and COX-2 are not well-defined. Here, we demonstrate that, macrophages infected with representative fungi Candida albicans, Aspergillus flavus or Aspergillus fumigatus or those treated with Curdlan, a selective agonist of pattern recognition receptor for fungi Dectin-1, displays increased expression of 5-LO, 15-LO and COX-2. Interestingly, Dectin-1-responsive Syk pathway activates mTOR-sonic hedgehog (SHH) signaling cascade to stimulate the expression of these lipid metabolizing enzymes. Loss-of-function analysis of the identified intermediaries indicates that while Syk-mTOR-SHH pathway-induced 5-LO and 15-LO suppressed the Dectin-l-responsive pro-inflammatory signature cytokines like TNE-alpha, IL-1 beta and IL-12, Syk-mTOR-SHH-induced COX-2 positively regulated these cytokines. Dectin-1-stimulated IL-6, however, is dependent on 5-LO, 15-LO and COX-2 activity. Together, the current study establishes Dectin-1-arbitrated host mediators that direct the differential regulation of immune responses during fungal infections and thus are potential candidates of therapeutic intervention. (C) 2015 Elsevier Ltd. All rights reserved.

Twinning induced enhancement of fracture toughness in ultrafine grained Hydroxyapatite-Calcium Titanate composites

Despite being highly bioactive and biocompatible, the limitations of monolithic hydroxyapatite (HA) include extremely low fracture toughness, poor electrical conductivity. While addressing these issues, the present study demonstrates how CaTiO3 (CT) addition to HA can be utilized to obtain a combination of long crack fracture toughness (1.7 MPa m(1/2) SEVNB technique) and flexural strength of 98-155 MPa (3-point bending) and a moderate tensile strength (diametral compression) of 17-36 MPa. The enhancement in fracture resistance in spark plasma sintered HA-CT composites has been explained in reference to the observed twin morphology. TEM reveals the presence of twins in CT grains due to 1800 rotation about 101]. The measured properties along with our earlier reports on biocompatibility and electrical properties make HA-CT suitable for bone tissue engineering applications. When compared with other competing HA-based biocomposites, HA-CT composites are found to have a better combination of properties useful for medium load bearing implant applications. (C) 2015 Elsevier Ltd. All rights reserved.

Bulk-Induced 1/f Noise at the Surface of Three-Dimensional Topological Insulators

Slow intrinsic fluctuations of resistance, also known as the flicker noise or 1/f-noise, in the surface transport of strong topological insulators (TIs) is a poorly understood phenomenon. Here, we have systematically explored the 1/f-noise in field-effect transistors (FET) of mechanically exfoliated Bi1.6Sb0.4Te2Se TI films when transport occurs predominantly via the surface states. We find that the slow kinetics of the charge disorder within the bulk of the TI induces mobility fluctuations at the surface, providing a new source of intrinsic 1/f-noise that is unique to bulk TI systems. At small channel thickness, the noise magnitude can be extremely small, corresponding to the phenomenological Hooge parameter gamma(H) as low as approximate to 10(-4), but it increases rapidly when channel thickness exceeds similar to 1 mu m. From the temperature (T)-dependence of noise, which displayed sharp peaks at characteristic values of T, we identified generation-recombination processes from interband transitions within the TI bulk as the dominant source of the mobility fluctuations in surface transport. Our experiment not only establishes an intrinsic microscopic origin of noise in TI surface channels, but also reveals a unique spectroscopic information on the impurity bands that can be useful in bulk TI systems in general.

Growth stress induced tunability of dielectric permittivity in thin films

Stress is inevitable during thin film growth. It is demonstrated here that the growth stress has a significant effect on the dielectric constant of high-k thin films. ZrO2 thin films were deposited on Ge by reactive direct current sputtering. Stress in these films was measured using in-situ curvature measurement tool. The growth stress was tuned from -2.8 to 0.1 GPa by controlling deposition rate. Dielectric permittivity of ZrO2 depends on temperature, phase, and stress. The correct combination of parameters-phase, texture, and stress-is shown to yield films with an equivalent oxide thickness of 8 angstrom. Growth stresses are shown to affect the dielectric constant both directly by affecting lattice parameter and indirectly through the effect on phase stability of ZrO2. (c) 2016 AIP Publishing LLC.

Iron(III) salicylates of dipicolylamine bases showing photo-induced anticancer activity and cytosolic localization

An iron(III) salicylate having a dipicolylamine base (andpa) with a photoactive anthracenyl moiety is prepared, characterized, and studied for its photo-induced anticancer activity and cellular localization in HeLa and MCF-7 cells. Its phenyl analogue is structurally characterized by X-ray crystallography. The complex has a ternary structure in which the dipicolylamine ligand and salicylic acid in dianionic form (sal) display respective tridentate and bidentate mode of coordination in Fe(sal)(phdpa)Cl] (1). Complex Fe(sal)(andpa)Cl] (2) having a pendant anthracenyl moiety shows significant photocytotoxicity in visible light (400-700 nm) giving IC50 values of 8.6 +/- 0.7 and 3.4 +/- 0.9 mu M in HeLa and MCF-7 cells, while being essentially nontoxic in the dark (IC50 > 100 mu M). The complex shows cytosolic localization in the cancer cells. Formation of hydroxyl radicals ((OH)-O-center dot) as the reactive oxygen species is evidenced from the pUC19 DNA photocleavage studies. (C) 2015 Elsevier Ltd. All rights reserved.

Edge states, spin transport, and impurity-induced local density of states in spin-orbit coupled graphene

We study graphene, which has both spin-orbit coupling (SOC), taken to be of the Kane-Mele form, and a Zeeman field induced due to proximity to a ferromagnetic material. We show that a zigzag interface of graphene having SOC with its pristine counterpart hosts robust chiral edge modes in spite of the gapless nature of the pristine graphene; such modes do not occur for armchair interfaces. Next we study the change in the local density of states (LDOS) due to the presence of an impurity in graphene with SOC and Zeeman field, and demonstrate that the Fourier transform of the LDOS close to the Dirac points can act as a measure of the strength of the spin-orbit coupling; in addition, for a specific distribution of impurity atoms, the LDOS is controlled by a destructive interference effect of graphene electrons which is a direct consequence of their Dirac nature. Finally, we study transport across junctions, which separates spin-orbit coupled graphene with Kane-Mele and Rashba terms from pristine graphene both in the presence and absence of a Zeeman field. We demonstrate that such junctions are generally spin active, namely, they can rotate the spin so that an incident electron that is spin polarized along some direction has a finite probability of being transmitted with the opposite spin. This leads to a finite, electrically controllable, spin current in such graphene junctions. We discuss possible experiments that can probe our theoretical predictions.

Nanoparticle induced miscibility in LCST polymer blends: critically assessing the enthalpic and entropic effects

The use of copolymer and polymer blends widened the possibility of creating materials with multilayered architectures. Hierarchical polymer systems with a wide array of micro and nanostructures are generated by thermally induced phase separation (TIPS) in partially miscible polymer blends. Various parameters like the interaction between the polymers, concentration, solvent/non-solvent ratio, and quenching temperature have to be optimized to obtain these micro/nanophase structures. Alternatively, the addition of nanoparticles is another strategy to design materials with desired hetero-phase structures. The dynamics of the polymer nanocomposite depends on the statistical ordering of polymers around the nanoparticle, which is dependent on the shape of the nanoparticle. The entropic loss due to deformation of polymer chains, like the repulsive interactions due to coiling and the attractive interactions in the case of swelling has been highlighted in this perspective article. The dissipative particle dynamics has been discussed and is correlated with the molecular dynamics simulation in the case of polymer blends. The Cahn Hillard Cook model on variedly shaped immobile fillers has shown difference in the propagation of the composition wave. The nanoparticle shape has a contributing effect on the polymer particle interaction, which can change the miscibility window in the case of these phase separating polymer blends. Quantitative information on the effect of spherical particles on the demixing temperature is well established and further modified to explain the percolation of rod shaped particles in the polymer blends. These models correlate well with the experimental observations in context to the dynamics induced by the nanoparticle in the demixing behavior of the polymer blend. The miscibility of the LCST polymer blend depends on the enthalpic factors like the specific interaction between the components, and the solubility product and the entropic losses occurring due to the formation of any favorable interactions. Hence, it is essential to assess the entropic and enthalpic interactions induced by the nanoparticles independently. The addition of nanoparticles creates heterogeneity in the polymer phase it is localized. This can be observed as an alteration in the relaxation behavior of the polymer. This changes the demixing behavior and the interaction parameter between the polymers. The compositional changes induced due to the incorporation of nanoparticles are also attributed as a reason for the altered demixing temperature. The particle shape anisotropy causes a direction dependent depletion, which changes the phase behavior of the blend. The polymer-grafted nanoparticles with varying grafting density show tremendous variation in the miscibility of the blend. The stretching of the polymer chains grafted on the nanoparticles causes an entropy penalty in the polymer blend. A comparative study on the different shaped particles is not available up to date for understanding these aspects. Hence, we have juxtaposed the various computational studies on nanoparticle dynamics, the shape effect of NPs on homopolymers and also the cases of various polymer blends without nanoparticles to sketch a complete picture on the effect of various particles on the miscibility of LCST blends.

Mycobacterium tuberculosis WhiB3 Responds to Vacuolar pH-induced Changes in Mycothiol Redox Potential to Modulate Phagosomal Maturation and Virulence.

The ability of Mycobacterium tuberculosis to resist intraphagosomal stresses, such as oxygen radicals and low pH, is critical for its persistence. Here, we show that a cytoplasmic redox sensor, WhiB3, and the major M. tuberculosis thiol, mycothiol (MSH), are required to resist acidic stress during infection. WhiB3 regulates the expression of genes involved in lipid anabolism, secretion, and redox metabolism, in response to acidic pH. Furthermore, inactivation of the MSH pathway subverted the expression of whiB3 along with other pH-specific genes in M. tuberculosis. Using a genetic biosensor of mycothiol redox potential (E-MSH), we demonstrated that a modest decrease in phagosomal pH is sufficient to generate redox heterogeneity in E-MSH of the M. tuberculosis population in a WhiB3-dependent manner. Data indicate that M. tuberculosis needs low pH as a signal to alter cytoplasmic E-MSH, which activates WhiB3-mediated gene expression and acid resistance. Importantly, WhiB3 regulates intraphagosomal pH by down-regulating the expression of innate immune genes and blocking phagosomal maturation. We show that this block in phagosomal maturation is in part due to WhiB3-dependent production of polyketide lipids. Consistent with these observations, Mtb Delta whiB3 displayed intramacrophage survival defect, which can be rescued by pharmacological inhibition of phagosomal acidification. Last, Mtb Delta whiB3 displayed marked attenuation in the lungs of guinea pigs. Altogether, our study revealed an intimate link between vacuolar acidification, redox physiology, and virulence in M. tuberculosis and discovered WhiB3 as crucial mediator of phagosomal maturation arrest and acid resistance in M. tuberculosis.

Designer porous antibacterial membranes derived from thermally induced phase separation of PS/PVME blends decorated with an electrospun nanofiber scaffold

We report the development of porous membranes by thermally induced phase separation of a PS/PVME (polystyrene/polyvinylmethyl ether]) blend, which is a typical LCST mixture. The morphology of the membrane after etching out the PVME phase was characterized by scanning electron microscopy. To give the membrane an antibacterial surface, polystyrene (PS) and polyvinyl(methyl ether)]-alt-maleic anhydride (PVME-MAH) with silver nanoparticles (nAg) were electrospun on the membrane surface. Pure water flux was evaluated by using a cross-flow membrane setup. The microgrooved fibers changed the flux across the membrane depending on the surface properties. The antibacterial properties of the membrane were confirmed by the reduction in the colony count of E. coli. The SEM images show the disruption of the bacterial cell membrane and the antibacterial mechanism was discussed.

Transgenic Drosophila model to study apolipoprotein E4-induced neurodegeneration

The epsilon 4 isoform of apolipoprotein E (ApoE4) that is involved in neuron-glial lipid metabolism has been demonstrated as the main genetic risk factor in late-onset of Alzheimer's disease. However, the mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We created a transgenic model of neurodegenerative disorder by expressing epsilon 3 and epsilon 4 isoforms of human ApoE in the Drosophila melanogaster. The genetic models exhibited progressive neurodegeneration, shortened lifespan and memory impairment. Genetic interaction studies between amyloid precursor protein and ApoE in axon pathology of the disease revealed that over expression of hApoE in Appl-expressing neurons of Drosophila brain causes neurodegeneration. Moreover, acute oxidative damage in the hApoE transgenic flies triggered a neuroprotective response of hApoE3 while chronic induction of oxidative damage accelerated the rate of neurodegeneration. This Drosophila model may facilitate analysis of the molecular and cellular events implicated in hApoE4 neurotoxicity. (C) 2015 Elsevier B.V. All rights reserved.