Biochemistry and Pharmacology - Research Publications
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ItemPhotophysical Identification of Three Kinds of Low-Energy Green Band Defects in Wide-Bandgap Polyfluorenes(AMER CHEMICAL SOC, 2019-04-04)Blue-light-emitting semiconductors based on polyfluorenes often exhibit an undesired green emission band. In this report, three well-defined oligofluorenes corresponding to three types of "defects" attributed to aggregation, keto formation, and chain entanglement, respectively, are systemically investigated to unveil the origins of the green emission band in fluorene-based materials. First, the optical properties of defect molecules in different states are studied. The defect associated with aggregation is absent in dilute solutions and in films doped at 0.01 wt % with poly(methyl methacrylate). Second, the dependence of the emission spectra on the solvent was monitored to compare the effects of the "keto-" and "chain-entanglement defect" molecules. The green emission of keto defects exhibited a strong dependence on solvent polarity, whereas this cannot be observed in case of chain-entanglement defect. Third, energy transfer between poly[4-(octyloxy)-9,9-diphenylfluoren-2,7-diyl]- co-[5-(octyloxy)-9,9-diphenyl-fluoren-2,7-diyl] and the keto or chain-entanglement defect molecules is illustrated. Compared to those of the chain-entanglement defect, the spectra of the keto defect molecule (1:10-3) show signs of defect emission at lower proportions. These investigations not only provide insight into the photophysics of oligofluorenes but also supply a new strategy to explore defects in semiconductor polymers, which will aid in the development of effective approaches to obtain stable, pure blue organic light-emitting diodes based on polyfluorenes.
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ItemPhotophysical and Fluorescence Anisotropic Behavior of Polyfluorene β-Conformation Films(AMER CHEMICAL SOC, 2018-01-18)We demonstrate a systematic visualization of the unique photophysical and fluorescence anisotropic properties of polyfluorene coplanar conformation (β-conformation) using time-resolved scanning confocal fluorescence imaging (FLIM) and fluorescence anisotropy imaging microscopy (FAIM) measurements. We observe inhomogeneous morphologies and fluorescence decay profiles at various micrometer-sized regions within all types of polyfluorene β-conformational spin-coated films. Poly(9,9-dioctylfluorene-2,7-diyl) (PFO) and poly[4-(octyloxy)-9,9-diphenylfluoren-2,7-diyl]-co-[5-(octyloxy)-9,9-diphenylfluoren-2,7-diyl] (PODPF) β-domains both have shorter lifetime than those of the glassy conformation for the longer effective conjugated length and rigid chain structures. Besides, β-conformational regions have larger fluorescence anisotropy for the low molecular rotational motion and high chain orientation, while the low anisotropy in glassy conformational regions shows more rotational freedom of the chain and efficient energy migration from amorphous regions to β-conformation as a whole. Finally, ultrastable ASE threshold in the PODPF β-conformational films also confirms its potential application in organic lasers. In this regard, FLIM and FAIM measurements provide an effective platform to explore the fundamental photophysical process of conformational transitions in conjugated polymer.
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ItemHighly Efficient Luminescent Solar Concentrators by Selective Alignment of Donor-Emitter Fluorophores(AMER CHEMICAL SOC, 2019-04-23)Vertically aligning fluorophores to the surface of a waveguide is known to be an effective approach to improve the optical quantum efficiency (OQE) of luminescent solar concentrators (LSCs). While the chromophore alignment assists waveguiding of the emitted photons to the LSC edges, it also significantly reduces the light-harvesting properties of the LSC. We report here a fluorophore pair consisting of a sphere-shaped energy donor and a rod-shaped emitter that was incorporated in LSCs to provide selective fluorophore alignment to address the reduced incident-light absorption issue. A liquid-crystal polymer matrix was used to perpendicularly align the rod-shaped acceptors to a favorable orientation for light guiding, while the sphere-shaped donor was randomly oriented to maintain its light-absorbing properties. The OQE of LSC devices with this selectively aligned donor-acceptor fluorophore system is 78% without significant loss of light-harvesting capability.
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ItemExtinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor(WILEY, 2015-05)We investigated the effects of extinguishing action-reward versus context-reward associations on drug-primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self-administer cocaine. We observed that daily context extinction (non-reinforced exposures to the cocaine-taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine-primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine-primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.
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ItemP2X7 Receptor-mediated Scavenger Activity of Mononuclear Phagocytes toward Non-opsonized Particles and Apoptotic Cells Is Inhibited by Serum Glycoproteins but Remains Active in Cerebrospinal Fluid(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2012-05-18)Rapid phagocytosis of non-opsonized particles including apoptotic cells is an important process that involves direct recognition of the target by multiple scavenger receptors including P2X7 on the phagocyte surface. Using a real-time phagocytosis assay, we studied the effect of serum proteins on this phagocytic process. Inclusion of 1-5% serum completely abolished phagocytosis of non-opsonized YG beads by human monocytes. Inhibition was reversed by pretreatment of serum with 1-10 mM tetraethylenepentamine, a copper/zinc chelator. Inhibitory proteins from the serum were determined as negatively charged glycoproteins (pI < 6) with molecular masses between 100 and 300 kDa. A glycoprotein-rich inhibitory fraction of serum not only abolished YG bead uptake but also inhibited phagocytosis of apoptotic lymphocytes or neuronal cells by human monocyte-derived macrophages. Three copper- and/or zinc-containing serum glycoproteins, ceruloplasmin, serum amyloid P-component, and amyloid precursor protein, were identified, and the purified proteins were shown to inhibit the phagocytosis of beads by monocytes as well as phagocytosis of apoptotic neuronal cells by macrophages. Human adult cerebrospinal fluid, which contains very little glycoprotein, had no inhibitory effect on phagocytosis of either beads or apoptotic cells. These data suggest for the first time that metal-interacting glycoproteins present within serum are able to inhibit the scavenger activity of mononuclear phagocytes toward insoluble debris and apoptotic cells.
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ItemIn silico prediction of antimalarial drug target candidates(ELSEVIER SCI LTD, 2012-12)The need for new antimalarials is persistent due to the emergence of drug resistant parasites. Here we aim to identify new drug targets in Plasmodium falciparum by phylogenomics among the Plasmodium spp. and comparative genomics to Homo sapiens. The proposed target discovery pipeline is largely independent of experimental data and based on the assumption that P. falciparum proteins are likely to be essential if (i) there are no similar proteins in the same proteome and (ii) they are highly conserved across the malaria parasites of mammals. This hypothesis was tested using sequenced Saccharomycetaceae species as a touchstone. Consecutive filters narrowed down the potential target space of P. falciparum to proteins that are likely to be essential, matchless in the human proteome, expressed in the blood stages of the parasite, and amenable to small molecule inhibition. The final set of 40 candidate drug targets was significantly enriched in essential proteins and comprised proven targets (e.g. dihydropteroate synthetase or enzymes of the non-mevalonate pathway), targets currently under investigation (e.g. calcium-dependent protein kinases), and new candidates of potential interest such as phosphomannose isomerase, phosphoenolpyruvate carboxylase, signaling components, and transporters. The targets were prioritized based on druggability indices and on the availability of in vitro assays. Potential inhibitors were inferred from similarity to known targets of other disease systems. The identified candidates from P. falciparum provide insight into biochemical peculiarities and vulnerable points of the malaria parasite and might serve as starting points for rational drug discovery.
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ItemThe Minimal Active Structure of Human Relaxin-2(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-10-28)H2 relaxin is a peptide hormone associated with a number of therapeutically relevant physiological effects, including regulation of collagen metabolism and multiple vascular control pathways. It is currently in phase III clinical trials for the treatment of acute heart failure due to its ability to induce vasodilation and influence renal function. It comprises 53 amino acids and is characterized by two separate polypeptide chains (A-B) that are cross-linked by three disulfide bonds. This size and complex structure represents a considerable challenge for the chemical synthesis of H2 relaxin, a major limiting factor for the exploration of modifications and derivatizations of this peptide, to optimize effect and drug-like characteristics. To address this issue, we describe the solid phase peptide synthesis and structural and functional evaluation of 24 analogues of H2 relaxin with truncations at the termini of its peptide chains. We show that it is possible to significantly truncate both the N and C termini of the B-chain while still retaining potent biological activity. This suggests that these regions are not critical for interactions with the H2 relaxin receptor, RXFP1. In contrast, truncations do reduce the activity of H2 relaxin for the related receptor RXFP2 by improving RXFP1 selectivity. In addition to new mechanistic insights into the function of H2 relaxin, this study identifies a critical active core with 38 amino acids. This minimized core shows similar antifibrotic activity as native H2 relaxin when tested in human BJ3 cells and thus represents an attractive receptor-selective lead for the development of novel relaxin therapeutics.
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ItemOpposing Actions of Extracellular Signal-regulated Kinase (ERK) and Signal Transducer and Activator of Transcription 3 (STAT3) in Regulating Microtubule Stabilization during Cardiac Hypertrophy(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-01-14)Excessive proliferation and stabilization of the microtubule (MT) array in cardiac myocytes can accompany pathological cardiac hypertrophy, but the molecular control of these changes remains poorly characterized. In this study, we examined MT stabilization in two independent murine models of heart failure and revealed increases in the levels of post-translationally modified stable MTs, which were closely associated with STAT3 activation. To explore the molecular signaling events contributing to control of the cardiac MT network, we stimulated cardiac myocytes with an α-adrenergic agonist phenylephrine (PE), and observed increased tubulin content without changes in detyrosinated (glu-tubulin) stable MTs. In contrast, the hypertrophic interleukin-6 (IL6) family cytokines increased both the glu-tubulin content and glu-MT density. When we examined a role for ERK in regulating cardiac MTs, we showed that the MEK/ERK-inhibitor U0126 increased glu-MT density in either control cardiac myocytes or following exposure to hypertrophic agents. Conversely, expression of an activated MEK1 mutant reduced glu-tubulin levels. Thus, ERK signaling antagonizes stabilization of the cardiac MT array. In contrast, inhibiting either JAK2 with AG490, or STAT3 signaling with Stattic or siRNA knockdown, blocked cytokine-stimulated increases in glu-MT density. Furthermore, the expression of a constitutively active STAT3 mutant triggered increased glu-MT density in the absence of hypertrophic stimulation. Thus, STAT3 activation contributes substantially to cytokine-stimulated glu-MT changes. Taken together, our results highlight the opposing actions of STAT3 and ERK pathways in the regulation of MT changes associated with cardiac myocyte hypertrophy.
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ItemBiosynthesis, Localization, and Macromolecular Arrangement of the Plasmodium falciparum Translocon of Exported Proteins (PTEX)(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2012-03-09)To survive within its host erythrocyte, Plasmodium falciparum must export hundreds of proteins across both its parasite plasma membrane and surrounding parasitophorous vacuole membrane, most of which are likely to use a protein complex known as PTEX (Plasmodium translocon of exported proteins). PTEX is a putative protein trafficking machinery responsible for the export of hundreds of proteins across the parasitophorous vacuole membrane and into the human host cell. Five proteins are known to comprise the PTEX complex, and in this study, three of the major stoichiometric components are investigated including HSP101 (a AAA(+) ATPase), a protein of no known function termed PTEX150, and the apparent membrane component EXP2. We show that these proteins are synthesized in the preceding schizont stage (PTEX150 and HSP101) or even earlier in the life cycle (EXP2), and before invasion these components reside within the dense granules of invasive merozoites. From these apical organelles, the protein complex is released into the host cell where it resides with little turnover in the parasitophorous vacuole membrane for most of the remainder of the following cell cycle. At this membrane, PTEX is arranged in a stable macromolecular complex of >1230 kDa that includes an ∼600-kDa apparently homo-oligomeric complex of EXP2 that can be separated from the remainder of the PTEX complex using non-ionic detergents. Two different biochemical methods undertaken here suggest that PTEX components associate as EXP2-PTEX150-HSP101, with EXP2 associating with the vacuolar membrane. Collectively, these data support the hypothesis that EXP2 oligomerizes and potentially forms the putative membrane-spanning pore to which the remainder of the PTEX complex is attached.
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ItemConservation of a Glycine-rich Region in the Prion Protein Is Required for Uptake of Prion Infectivity(AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2010-06-25)Prion diseases are associated with the misfolding of the endogenously expressed prion protein (designated PrP(C)) into an abnormal isoform (PrP(Sc)) that has infectious properties. The hydrophobic domain of PrP(C) is highly conserved and contains a series of glycine residues that show perfect conservation among all species, strongly suggesting it has functional and evolutionary significance. These glycine residues appear to form repeats of the GXXXG protein-protein interaction motif (two glycines separated by any three residues); the retention of these residues is significant and presumably relates to the functionality of PrP(C). Mutagenesis studies demonstrate that minor alterations to this highly conserved region of PrP(C) drastically affect the ability of cells to uptake and replicate prion infection in both cell and animal bioassay. The localization and processing of mutant PrP(C) are not affected, although in vitro and in vivo studies demonstrate that this region is not essential for interaction with PrP(Sc), suggesting these residues provide conformational flexibility. These data suggest that this region of PrP(C) is critical in the misfolding process and could serve as a novel, species-independent target for prion disease therapeutics.