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Sample records for a2 mimetic u46619

  1. Resolvin E1, resolvin D1 and resolvin D2 inhibit constriction of rat thoracic aorta and human pulmonary artery induced by the thromboxane mimetic U46619.

    PubMed

    Jannaway, Melanie; Torrens, Christopher; Warner, Jane A; Sampson, Anthony P

    2018-04-01

    The ω-6 fatty acid-derived lipid mediators such as prostanoids, thromboxane and leukotrienes have well-established roles in regulating both inflammation and smooth muscle contractility. Resolvins are derived from ω-3 fatty acids and have important roles in promoting the resolution of inflammation, but their activity on smooth muscle contractility is unknown. We investigated whether resolvin E1 (RvE1), resolvin D1 (RvD1) and resolvin D2 (RvD2) can modulate contractions of isolated segments of rat thoracic aorta (RTA) or human pulmonary artery (HPA) induced by the α 1 -adrenoceptor agonist phenylephrine or the stable thromboxane A 2 mimetic U46619. Contractile responses in RTA and HPA were measured using wire myography. Receptor expression was investigated by immunohistochemistry. Constriction of RTA segments by U46619, but not by phenylephrine, was significantly inhibited by pretreatment for 1 or 24 h with 10-100 nM RvE1, RvD1 or RvD2. The inhibitory effect of RvE1 was partially blocked by a chemerin receptor antagonist (CCX832). RvE1 at only 1-10 nM also significantly inhibited U46619-induced constriction of HPA segments, and the chemerin receptor, GPR32 and FPR2/ALX were identified in HPA smooth muscle. These data suggest that resolvins or their mimetics may prove useful novel therapeutics in diseases such as pulmonary arterial hypertension, which are characterized by increased thromboxane contractile activity. © 2018 The British Pharmacological Society.

  2. Activation of CB1receptors by 2-arachidonoylglycerol attenuates vasoconstriction induced by U46619 and angiotensin II in human and rat pulmonary arteries.

    PubMed

    Karpińska, Olga; Baranowska-Kuczko, Marta; Kloza, Monika; Ambroz Ewicz, Ewa; Kozłowski, Tomasz; Kasacka, Irena; Malinowska, Barbara; Kozłowska, Hanna

    2017-06-01

    Recent evidence suggests that endocannabinoids acting via cannabinoid CB 1 receptors may modulate vascular responses of various vasoconstrictors in the rodent systemic vasculature. The aim of the study was to investigate whether endocannabinoids modulate the contractile responses evoked by a thromboxane A 2 analog (U46619), angiotensin II (ANG II), serotonin (5-HT), and phenylephrine, which stimulate distinct G q/11 protein-coupled receptors (thromboxane, ANG II type 1, 5-HT 2 , and α 1 -adrenergic receptors) in isolated endothelium-intact human and rat pulmonary arteries (hPAs and rPAs, respectively). The CB 1 receptor antagonist AM251 (1 μM) and diacylglycerol lipase (2-arachidonoylglycerol synthesis enzyme) inhibitor RHC80267 (40 μM) enhanced contractions induced by U46619 in hPAs and rPAs and by ANG II in rPAs in an endothelium-dependent manner. AM251 did not influence vasoconstrictions induced by 5-HT or phenylephrine in rPAs. The monoacylglycerol lipase (2-arachidonoylglycerol degradation enzyme) inhibitor JZL184 (1 μM), but not the fatty acid amide hydrolase (anandamide degradation enzyme) inhibitor URB597 (1 μM), attenuated contractions evoked by U46619 in hPAs and rPAs and ANG II in rPAs. 2-Arachidonoylglycerol concentration-dependently induced relaxation of hPAs, which was inhibited by endothelium denudation or AM251 and enhanced by JZL184. Expression of CB 1 receptors was confirmed in hPAs and rPAs using Western blotting and immunohistochemistry. The present study shows the protective interaction between the endocannabinoid system and vasoconstriction in response to U46619 and ANG II in the human and rat pulmonary circulation. U46619 and ANG II may stimulate rapid endothelial release of endocannabinoids (mainly 2-arachidonoylglycerol), leading to CB 1 receptor-dependent and/or CB 1 receptor-independent vasorelaxation, which in the negative feedback mechanism reduces later agonist-induced vasoconstriction. Copyright © 2017 the American Physiological

  3. TRPA1 and TRPV1 contribute to propofol-mediated antagonism of U46619-induced constriction in murine coronary arteries

    PubMed Central

    Sinha, Sayantani; Showalter, Loral E.; Andrei, Spencer R.

    2017-01-01

    Background Transient receptor potential (TRP) ion channels have emerged as key components contributing to vasoreactivity. Propofol, an anesthetic is associated with adverse side effects including hypotension and acute pain upon infusion. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs. Methods Hearts were excised from anesthetized mice and coronary arterioles were dissected from control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). Isolated microvessels were cannulated and secured in a temperature-controlled chamber and allowed to equilibrate for 1 hr. Vasoreactivity studies were performed in microvessels pre-constricted with U46619 to assess the dose-dependent relaxation effects of propofol on coronary microvascular tone. Results Propofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice. Conclusions TRPA1 and TRPV1 appear to contribute to the propofol-mediated antagonism of U46619-induced constriction in murine coronary microvessels that involves activation of NOS and BKCa. PMID:28644897

  4. The angiotensin II AT1 receptor antagonist irbesartan prevents thromboxane A2-induced vasoconstriction in the rat hind-limb vascular bed in vivo.

    PubMed

    Fukuhara, M; Neves, L A; Li, P; Diz, D I; Ferrario, C M; Brosnihan, K B

    2001-03-01

    We studied the vasoconstrictor effects of the thromboxane A2 (TxA2) analogue U46619 in the perfused hind limb of rats under constant flow before and after intravenous injection of irbesartan, an angiotensin II AT1 receptor antagonist, to test whether irbesartan interacts in vivo with the thromboxane A2/prostaglandin endoperoxidase H2 (TxA2/PGH2) receptor. Male Sprague-Dawley rats (n = 15, body weight 350-420 g) were anesthetized with thiobutabarbital sodium (Inactin, 100 mg/kg intraperitoneally). Regional vascular responses to U46619 (0.5 and 1.0 microg) were investigated in the rat hind quarter under conditions of controlled flow before and after administration of irbesartan (10 mg/kg, intravenously). In addition, to test the specificity of the effect of irbesartan on U46619, phenylephrine (0.5, 1.0 microg) and another AT1 receptor antagonist, candesartan CV11974 (0.3 mg/kg, intravenously) were used. The dose-dependent increases in hind-limb perfusion pressure produced by U46619 were significantly attenuated by prior injection of irbesartan, at a dose that blocked the angiotensin II (Ang II) pressor responses. The specificity for the response was shown with the demonstrations that the increase in vascular resistance produced by phenylephrine was unchanged by irbesartan and, furthermore, that the increase in vascular resistance produced by U46619 was unchanged by another AT1 receptor antagonist, candesartan. This study demonstrates that irbesartan interacts at the TxA2/PGH2 receptor in the rat's hind limb in vivo, to modify changes in local regional vascular resistance. The dual antagonistic actions of irbesartan, acting at both AT1 and TxA2 receptors in blood vessels, may overall enhance its therapeutic profile in the treatment of hypertension.

  5. TRA-418, a thromboxane A2 receptor antagonist and prostacyclin receptor agonist, inhibits platelet-leukocyte interaction in human whole blood.

    PubMed

    Miyamoto, Mitsuko; Ohno, Michihiro; Yamada, Naohiro; Ohtake, Atsushi; Matsushita, Teruo

    2010-10-01

    TRA-418, a compound with both thromboxane A2 receptor (TP receptor) antagonistic and prostacyclin receptor (IP receptor) agonistic activities, was synthesised in our laboratory as a new antithrombotic agent. In this study, we examined the effects of TRA-418 on platelet-leukocyte interactions in human whole blood. Platelet-leukocyte interactions were induced by U-46619 in the presence of epinephrine (U-46619 + epinephrine) or with thrombin receptor agonist peptide 1-6 (TRAP). Platelet-leukocyte interactions were assessed by flow cytometry, with examination of both platelet-neutrophil and platelet-monocyte complexes. In a control experiment, the TP receptor antagonist SQ-29548 significantly inhibited the induction of platelet-leukocyte complexes by the combination of U-46619 and epinephrine, but not TRAP-induced formation of platelet-leukocyte complexes. Conversely, the IP receptor agonist beraprost sodium inhibited platelet-leukocyte complex formation induced by both methods, although the IC50 values of beraprost sodium for U-46619 + epinephrine were at least 10-fold greater than for TRAP. Under such conditions, TRA-418 inhibited both U-46619 + epinephrine-induced and TRAP-induced platelet-leukocyte complex formation in a concentration-dependent manner, in a similar range. These results suggest that TRA-418 exerts its inhibitory effects on platelet-leukocyte interactions by acting as a TP receptor antagonist as well as an IP receptor agonist in an additive or synergistic manner. These inhibitory effects of TRA-418 on formation of platelet-leukocyte complexes suggest the compound is beneficial effects as an antithrombotic agent.

  6. Effect on human platelet aggregation of phospholipase A2 purified from Heloderma horridum (beaded lizard) venom.

    PubMed

    Huang, T F; Chiang, H S

    1994-02-10

    By means of gel filtration, ionic exchange chromatography and DEAE-column HPLC, an acidic phospholipase A2 (PLA2) was purified from beaded lizard (Heloderma horridum) venom. The purified PLA is a single-chain polypeptide, consisting of about 163 amino acid residues with a molecular mass of 19,000 Da as calculated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and amino acid analysis. HHV-PLA showed a rather specific inhibitory effect on platelet aggregation induced by U46619 and epinephrine in human platelet-rich plasma in a dose- and time-dependent manner, whereas it had little effect on collagen- and ADP-induced aggregation. ATP-release reaction induced by various agonists were dose- and time-dependently inhibited by HHV-PLA, even though platelet aggregation was apparently not affected in human washed platelets. When HHV-PLA was chemically modified with p-bromophenacyl bromide, both of its enzymatic activity and antiplatelet activity were lost. Furthermore, exogenous lysophosphatidylcholine and HHV-PLA treated phosphatidylcholine inhibited platelet aggregation induced by U46619 in human washed platelets. In conclusion, PLA enzyme from H. horridum venom inhibits exclusively U46619- or thromboxane-induced platelet aggregation of human platelet-rich plasma probably by virtue of their PLA enzymatic activity on plasma phospholipids, converting phospholipids (e.g., phosphatidylcholine) into lysophospholipids, which in turn interfere with the coupling of TXA2 receptor and its signalling transduction system.

  7. Kinetics of prostaglandin E2 and thromboxane A2 synthesis and suppression of PHA-stimulated peripheral blood mononuclear leucocytes.

    PubMed

    Awara, W; Hillier, K; Jones, D

    1986-12-01

    The immunomodulatory effects of thromboxane A2 and prostaglandin E2 on peripheral blood mononuclear leucocytes stimulated with PHA in vitro, and the relationship of this to the time-course of their synthesis in culture, were investigated using prostaglandin E2, a thromboxane A2 synthesis inhibitor (UK37248), a thromboxane A2 mimic (U46619) and a thromboxane A2 receptor blocker (EP045). The inhibitory effect of prostaglandin E2 on PHA-induced human peripheral blood mononuclear leucocyte proliferation diminishes if the addition of PGE2 is delayed. If added 4 hr after a maximum concentration of PHA (5 micrograms/ml), the effect of PGE2 was reduced by 60%. If a submaximal concentration of PHA (1 microgram/ml) was used, the effect of PGE2 was not reduced if added 4 hr later but fell by about 60% after 16 hr. UK37248 moderately inhibited PHA-induced activation while substantially inhibiting thromboxane A2 synthesis and simultaneously enhancing PGE2 synthesis. The enhanced accumulation of PGE2 occurs while sensitivity to PGE2 is dropping. U46619, exogenously applied as a thromboxane A2 mimic, inhibited PHA-induced activation at concentrations that did not significantly alter PGE2 synthesis. EP045, which may modulate the effects of endogenous thromboxane A2 by blocking receptors, did not alter PHA-induced activation. We conclude that thromboxane A2 may have a role in inhibiting PHA-induced activation on the basis of the effect of U46619. However, this study highlights difficulties in utilizing prostaglandin and thromboxane receptor and synthesis inhibitors to examine their endogenous role in the modulation of mitogen-induced activation in vitro. If sensitivity to the purported endogenous substance is limited to the early stages of culture and if only low levels are synthesized at this early stage, then blocking drugs would have little effect.

  8. Kinetics of prostaglandin E2 and thromboxane A2 synthesis and suppression of PHA-stimulated peripheral blood mononuclear leucocytes.

    PubMed Central

    Awara, W; Hillier, K; Jones, D

    1986-01-01

    The immunomodulatory effects of thromboxane A2 and prostaglandin E2 on peripheral blood mononuclear leucocytes stimulated with PHA in vitro, and the relationship of this to the time-course of their synthesis in culture, were investigated using prostaglandin E2, a thromboxane A2 synthesis inhibitor (UK37248), a thromboxane A2 mimic (U46619) and a thromboxane A2 receptor blocker (EP045). The inhibitory effect of prostaglandin E2 on PHA-induced human peripheral blood mononuclear leucocyte proliferation diminishes if the addition of PGE2 is delayed. If added 4 hr after a maximum concentration of PHA (5 micrograms/ml), the effect of PGE2 was reduced by 60%. If a submaximal concentration of PHA (1 microgram/ml) was used, the effect of PGE2 was not reduced if added 4 hr later but fell by about 60% after 16 hr. UK37248 moderately inhibited PHA-induced activation while substantially inhibiting thromboxane A2 synthesis and simultaneously enhancing PGE2 synthesis. The enhanced accumulation of PGE2 occurs while sensitivity to PGE2 is dropping. U46619, exogenously applied as a thromboxane A2 mimic, inhibited PHA-induced activation at concentrations that did not significantly alter PGE2 synthesis. EP045, which may modulate the effects of endogenous thromboxane A2 by blocking receptors, did not alter PHA-induced activation. We conclude that thromboxane A2 may have a role in inhibiting PHA-induced activation on the basis of the effect of U46619. However, this study highlights difficulties in utilizing prostaglandin and thromboxane receptor and synthesis inhibitors to examine their endogenous role in the modulation of mitogen-induced activation in vitro. If sensitivity to the purported endogenous substance is limited to the early stages of culture and if only low levels are synthesized at this early stage, then blocking drugs would have little effect. PMID:3468061

  9. Flavonoids inhibit the platelet TxA2 signalling pathway and antagonize TxA2 receptors (TP) in platelets and smooth muscle cells

    PubMed Central

    Guerrero, José A; Navarro-Nuñez, Leyre; Lozano, María L; Martínez, Constantino; Vicente, Vicente; Gibbins, Jonathan M; Rivera, José

    2007-01-01

    What is already known about this subject Flavonoids are largely recognized as potential inhibitors of platelet function, through nonspecific mechanisms such as antioxidant activity and/or inhibition of several enzymes and signalling proteins. In addition, we, and few others, have shown that certain antiaggregant flavonoids may behave as specific TXA2 receptor (TP) ligands in platelets. Whether flavonoids interact with TP isoforms in other cell types is not known, and direct evidence that flavonoid–TP interaction inhibits signalling downstream TP has not been shown. What this study adds This study first demonstrates that certain flavonoids behave as ligands for both TP isoforms, not only in platelets, but also in human myometrium and in TP-transfected HEK 293T cells. Differences in the effect of certain flavonoids in platelet signalling, induced by either U46619 or thrombin, suggest that abrogation of downstream TP signalling is related to their specific blockage of the TP, rather than to a nonspecific effect on tyrosine kinases or other signalling proteins. Aims Flavonoids may affect platelet function by several mechanisms, including antagonism of TxA2 receptors (TP). These TP are present in many tissues and modulate different signalling cascades. We explored whether flavonoids affect platelet TP signalling, and if they bind to TP expressed in other cell types. Methods Platelets were treated with flavonoids, or other selected inhibitors, and then stimulated with U46619. Similar assays were performed in aspirinized platelets activated with thrombin. Effects on calcium release were analysed by fluorometry and changes in whole protein tyrosine phosphorylation and activation of ERK 1/2 by Western blot analysis. The binding of flavonoids to TP in platelets, human myometrium and TPα- and TPβ-transfected HEK 293T cells was explored using binding assays and the TP antagonist 3H-SQ29548. Results Apigenin, genistein, luteolin and quercetin impaired U46619-induced calcium

  10. Instabilities in mimetic matter perturbations

    SciTech Connect

    Firouzjahi, Hassan; Gorji, Mohammad Ali; Mansoori, Seyed Ali Hosseini, E-mail: firouz@ipm.ir, E-mail: gorji@ipm.ir, E-mail: shosseini@shahroodut.ac.ir, E-mail: shossein@ipm.ir

    2017-07-01

    We study cosmological perturbations in mimetic matter scenario with a general higher derivative function. We calculate the quadratic action and show that both the kinetic term and the gradient term have the wrong sings. We perform the analysis in both comoving and Newtonian gauges and confirm that the Hamiltonians and the associated instabilities are consistent with each other in both gauges. The existence of instabilities is independent of the specific form of higher derivative function which generates gradients for mimetic field perturbations. It is verified that the ghost instability in mimetic perturbations is not associated with the higher derivative instabilitiesmore » such as the Ostrogradsky ghost.« less

  11. Smac mimetics as IAP antagonists.

    PubMed

    Fulda, Simone

    2015-03-01

    As the Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in human cancers, they represent promising targets for therapeutic intervention. Small-molecule inhibitors of IAP proteins mimicking the endogenous IAP antagonist Smac, called Smac mimetics, neutralize IAP proteins and thereby promote the induction of cell death. Smac mimetics have been shown in preclinical models of human cancer to directly trigger cancer cell death or to sensitize for cancer cell death induced by a variety of cytotoxic stimuli. Smac mimetics are currently undergoing clinical evaluation in phase I/II trials, demonstrating that therapeutic targeting of IAP proteins has reached the clinical stage. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. Neural ECM mimetics.

    PubMed

    Estrada, Veronica; Tekinay, Ayse; Müller, Hans Werner

    2014-01-01

    The consequence of numerous neurological disorders is the significant loss of neural cells, which further results in multilevel dysfunction or severe functional deficits. The extracellular matrix (ECM) is of tremendous importance for neural regeneration mediating ambivalent functions: ECM serves as a growth-promoting substrate for neurons but, on the other hand, is a major constituent of the inhibitory scar, which results from traumatic injuries of the central nervous system. Therefore, cell and tissue replacement strategies on the basis of ECM mimetics are very promising therapeutic interventions. Numerous synthetic and natural materials have proven effective both in vitro and in vivo. The closer a material's physicochemical and molecular properties are to the original extracellular matrix, the more promising its effectiveness may be. Relevant factors that need to be taken into account when designing such materials for neural repair relate to receptor-mediated cell-matrix interactions, which are dependent on chemical and mechanical sensing. This chapter outlines important characteristics of natural and synthetic ECM materials (scaffolds) and provides an overview of recent advances in design and application of ECM materials for neural regeneration, both in therapeutic applications and in basic biological research.

  13. Cosmological dynamics of mimetic gravity

    NASA Astrophysics Data System (ADS)

    Dutta, Jibitesh; Khyllep, Wompherdeiki; Saridakis, Emmanuel N.; Tamanini, Nicola; Vagnozzi, Sunny

    2018-02-01

    We present a detailed investigation of the dynamical behavior of mimetic gravity with a general potential for the mimetic scalar field. Performing a phase-space and stability analysis, we show that the scenario at hand can successfully describe the thermal history of the universe, namely the successive sequence of radiation, matter, and dark-energy eras. Additionally, at late times the universe can either approach a de Sitter solution, or a scaling accelerated attractor where the dark-matter and dark-energy density parameters are of the same order, thus offering an alleviation of the cosmic coincidence problem. Applying our general analysis to various specific potential choices, including the power-law and the exponential ones, we show that mimetic gravity can be brought into good agreement with the observed behavior of the universe. Moreover, with an inverse square potential we find that mimetic gravity offers an appealing unified cosmological scenario where both dark energy and dark matter are characterized by a single scalar field, and where the cosmic coincidence problem is alleviated.

  14. Bio-mimetic Flow Control

    NASA Astrophysics Data System (ADS)

    Choi, Haecheon

    2009-11-01

    Bio-mimetic engineering or bio-mimetics is the application of biological methods and systems found in nature to the study and design of engineering systems and modern technology (from Wikipedia). The concept itself is old, but successful developments have been made recently, especially in the research field of flow control. The objective of flow control based on the bio-mimetic approach is to develop novel concepts for reducing drag, increasing lift and enhancing aerodynamic performance. For skin friction reduction, a few ideas have been suggested such as the riblet from shark, compliant surface from dolphin, microbubble injection and multiple front-body curvature from penguin, and V-shaped protrusion from sailfish. For form drag reduction, several new attempts have been also made recently. Examples include the V-shaped spanwise grooves from saguaro cactus, overall shape of box fish, longitudinal grooves on scallop shell, bill of swordfish, hooked comb on owl wing, trailing-edge protrusion on dragonfly wing, and fillet. For the enhancement of aerodynamic performance, focuses have been made on the birds, fish and insects: e.g., double layered feather of landing bird, leading-edge serration of humpback-whale flipper, pectoral fin of flying fish, long tail on swallowtail-butterfly wing, wing flapping motion of dragonfly, and alula in birds. Living animals adapt their bodies to better performance in multi purposes, but engineering requires single purpose in most cases. Therefore, bio-mimetic approaches often produce excellent results more than expected. However, they are sometimes based on people's wrong understanding of nature and produce unwanted results. Successes and failures from bio-mimetic approaches in flow control will be discussed in the presentation.

  15. Triplatin, a platelet aggregation inhibitor from the salivary gland of the triatomine vector of Chagas Disease, binds to TXA2 but does not interact with GPVI

    PubMed Central

    Ma, Dongying; Assumpção, Teresa C. F.; Li, Yuan; Andersen, John F.; Ribeiro, José M.C.; Francischetti, Ivo M.B.

    2012-01-01

    Salivary glands from hematophagous animals express a notable diversity of negative modulators of platelet function. Triplatin is an inhibitor of collagen-induced platelet aggregation which has been described as an antagonist of glycoprotein VI (GPVI). Because triplatin displays sequence homology to members of the lipocalin family of proteins, we investigated whether triplatin mechanism of action could be explained by interaction with pro-hemostatic prostaglandins. Our results demonstrate that triplatin inhibits platelet aggregation induced by low doses of collagen, thromboxane A2 (TXA2) mimetic (U46619), and arachidonic acid (AA). On the other hand, it does not inhibit platelet aggregation by convulxin, PMA, or low-dose ADP. Isothermal titration calorimetry (ITC) revealed that triplatin binds AA, cTXA2, TXB2, U46619 or PGH2 mimetic (U51605). Consistent with its ligand specificity, triplatin induces relaxation of rat aorta contracted with U46619. Triplatin also interacts with PGF2α and PGJ2, but not with leukotrienes, AA or biogenic amines. Surface plasmon resonance experiments failed to demonstrate interaction of triplatin with GPVI; it also did to inhibit platelet adhesion to fibrillar or soluble collagen. Because triplatin displays sequence similarity to apolipoprotein D (ApoD)—a lipocalin associated with HDL, it was tested as a putative TXA2-binding molecule. ITC failed to demonstrate binding of ApoD to all prostanoids described above, or to AA. Furthermore, ApoD was devoid of inhibitory properties towards platelets activation by AA, collagen, or U46619. In conclusion, Triplatin mechanism of action has been elucidate without ambiguity as a novel TXA2- and PGF2α- binding protein. It conceivably blocks platelet aggregation and vasoconstriction, thus contributing to successful blood feeding at the vector-host interface. PMID:22159626

  16. Heparin mimetics with anticoagulant activity.

    PubMed

    Nahain, Abdullah Al; Ignjatovic, Vera; Monagle, Paul; Tsanaktsidis, John; Ferro, Vito

    2018-02-15

    Heparin, a sulfated polysaccharide belonging to the glycosaminoglycan family, has been widely used as an anticoagulant drug for decades and remains the most commonly used parenteral anticoagulant in adults and children. However, heparin has important clinical limitations and is derived from animal sources which pose significant safety and supply problems. The ever growing shortage of the raw material for heparin manufacturing may become a very significant issue in the future. These global limitations have prompted much research, especially following the recent well-publicized contamination scandal, into the development of alternative anticoagulants derived from non-animal and/or totally synthetic sources that mimic the structural features and properties of heparin. Such compounds, termed heparin mimetics, are also needed as anticoagulant materials for use in biomedical applications (e.g., stents, grafts, implants etc.). This review encompasses the development of heparin mimetics of various structural classes, including synthetic polymers and non-carbohydrate small molecules as well as sulfated oligo- and polysaccharides, and fondaparinux derivatives and conjugates, with a focus on developments in the past 10 years. © 2018 Wiley Periodicals, Inc.

  17. Unimodular mimetic F(R) inflation

    NASA Astrophysics Data System (ADS)

    Odintsov, S. D.; Oikonomou, V. K.

    2016-07-01

    We propose the unimodular-mimetic F(R) gravity theory, to resolve cosmological constant problem and dark matter problem in a unified geometric manner. We demonstrate that such a theory naturally admits accelerating universe evolution. Furthermore, we construct unimodular-mimetic F(R) inflationary cosmological scenarios compatible with the Planck and BICEP2/Keck-Array observational data. We also address the graceful exit issue, which is guaranteed by the existence of unstable de Sitter vacua.

  18. Thromboxane A2 Receptor Inhibition Suppresses Multiple Myeloma Cell Proliferation by Inducing p38/c-Jun N-terminal Kinase (JNK) Mitogen-activated Protein Kinase (MAPK)-mediated G2/M Progression Delay and Cell Apoptosis*

    PubMed Central

    Liu, Qian; Tao, Bo; Liu, Guizhu; Chen, Guilin; Zhu, Qian; Yu, Ying; Yu, Yu; Xiong, Hong

    2016-01-01

    Multiple myeloma (MM) is a plasma cell malignancy without effective therapeutics. Thromboxane A2 (TxA2)/TxA2 receptor (T prostanoid receptor (TP)) modulates the progression of some carcinomas; however, its effects on MM cell proliferation remain unclear. In this study, we evaluated cyclooxygenase (COX) enzymes and downstream prostaglandin profiles in human myeloma cell lines RPMI-8226 and U-266 and analyzed the effects of COX-1/-2 inhibitors SC-560 and NS-398 on MM cell proliferation. Our observations implicate COX-2 as being involved in modulating cell proliferation. We further incubated MM cells with prostaglandin receptor antagonists or agonists and found that only the TP antagonist, SQ29548, suppressed MM cell proliferation. TP silencing and the TP agonist, U46619, further confirmed this finding. Moreover, SQ29548 and TP silencing promoted MM cell G2/M phase delay accompanied by reducing cyclin B1/cyclin-dependent kinase-1 (CDK1) mRNA and protein expression. Notably, cyclin B1 overexpression rescued MM cells from G2/M arrest. We also found that the TP agonist activated JNK and p38 MAPK phosphorylation, and inhibitors of JNK and p38 MAPK depressed U46619-induced proliferation and cyclin B1/CDK1 protein expression. In addition, SQ29548 and TP silencing led to the MM cell apoptotic rate increasing with improving caspase 3 activity. The knockdown of caspase 3 reversed the apoptotic rate. Taken together, our results suggest that TxA2/TP promotes MM cell proliferation by reducing cell delay at G2/M phase via elevating p38 MAPK/JNK-mediated cyclin B1/CDK1 expression and hindering cell apoptosis. The TP inhibitor has potential as a novel agent to target kinase cascades for MM therapy. PMID:26724804

  19. [Incretin mimetic drugs: therapeutic positioning].

    PubMed

    López Simarro, F

    2014-07-01

    Type 2 diabetes is a chronic and complex disease, due to the differences among affected individuals, which affect choice of treatment. The number of drug families has increased in the last few years, and these families have widely differing mechanisms of action, which contributes greatly to the individualization of treatment according to the patient's characteristics and comorbidities. The present article discusses incretin mimetic drugs. Their development has been based on knowledge of the effects of natural incretin hormones: GLP-1 (glucagon-like peptide 1), GIP (glucose-dependent insulinotropic peptide) and dipeptidyl peptidase enzyme 4 (DPP4), which rapidly degrade them in the systemic circulation. This group is composed of 2 different types of molecules: GLP-1 analogs and DPP4 enzyme inhibitors. The benefits of these molecules include a reduction in plasma glucose without the risk of hypoglycemias or weight gain. There are a series of questions that require new studies to establish a possible association between the use of these drugs and notification of cases of pancreatitis, as well as their relationship with pancreatic and thyroid cancer. Also awaited is the publication of several studies that will provide information on the relationship between these drugs and cardiovascular risk in people with diabetes. All these questions will probably be progressively elucidated with greater experience in the use of these drugs. Copyright © 2014 Elsevier España, S.L.U. y Sociedad Española de Medicina Rural y Generalista (SEMERGEN). All rights reserved.

  20. Cosmological perturbations in mimetic Horndeski gravity

    SciTech Connect

    Arroja, Frederico; Bartolo, Nicola; Karmakar, Purnendu

    2016-04-01

    We study linear scalar perturbations around a flat FLRW background in mimetic Horndeski gravity. In the absence of matter, we show that the Newtonian potential satisfies a second-order differential equation with no spatial derivatives. This implies that the sound speed for scalar perturbations is exactly zero on this background. We also show that in mimetic G {sup 3} theories the sound speed is equally zero. We obtain the equation of motion for the comoving curvature perturbation (first order differential equation) and solve it to find that the comoving curvature perturbation is constant on all scales in mimetic Horndeski gravity. Wemore » find solutions for the Newtonian potential evolution equation in two simple models. Finally we show that the sound speed is zero on all backgrounds and therefore the system does not have any wave-like scalar degrees of freedom.« less

  1. Cardioprotection by Conditioning Mimetic Drugs.

    PubMed

    Santillo, Elpidio; Migale, Monica; Postacchini, Demetrio; Balestrini, Fabrizio; Incalzi, Raffaele Antonelli

    2016-01-01

    At present, ischemic heart disease (IHD) is one of the main causes of morbidity and mortality world-wide. An important insight into both IHD pathophysiology and cardioprotection was achieved in 1986 when Murry et al. described for the first time the ischemic preconditioning (IP). IP can be defined as an innate phenomenon by which brief episodes of ischemia confer protection to a tissue from a subsequent more protracted ischemic insult. Suggested mechanisms explaining IP comprise the action of circulating substances (e.g. adenosine, bradykinin, nitric oxide). These mediators are released after a prolonged ischemic stress, causing activation of molecular pathways that induce favorable posttranslational changes of proteins and adaptive modifications in genetic expression. Briefly review evidences from clinical studies on drugs that exert their effects by mimicking IP, discussing their therapeutic properties and the potential clinical employment in order to obtain cardioprotection. Literature regarding IP mimicking pharmacological agents was searched in Medline and Google Scholar. Authors reviewed relevant researches in English language including both clinical studies and reviews of clinical studies published from 1986 to 2016. Several pharmacological agents reproducing IP protective actions have been evaluated in many clinical trials. Examined molecules include adenosine, nicorandil and atrial natriuretic peptide. Interestingly IP mimicking effects of drugs have been also analyzed perioperatively in the context of ischaemia-reperfusion heart injury. Moreover evidences suggest that also some anaesthetic drugs (especially volatile agents) are able to provide myocardial protection by inducing IP. Drugs capable of mimicking IP exhibit a high therapeutic potential because of their properties of eliciting an effective cardioprotective signaling. Future studies should clarify the optimal doses and timing of administration of IP mimetic agents in order to favor the advent of

  2. Thrombopoietin mimetics for patients with myelodysplastic syndromes.

    PubMed

    Dodillet, Helga; Kreuzer, Karl-Anton; Monsef, Ina; Skoetz, Nicole

    2017-09-30

    Myelodysplastic syndrome (MDS) is one of the most frequent haematologic malignancies of the elderly population and characterised by progenitor cell dysplasia with ineffective haematopoiesis and a high rate of transformation to acute myeloid leukaemia (AML). Thrombocytopenia represents a common problem for patients with MDS. ranging from mild to serious bleeding events and death. To manage thrombocytopenia, the current standard treatment includes platelet transfusion, unfortunately leading to a range of side effects. Thrombopoietin (TPO) mimetics represent an alternative treatment option for MDS patients with thrombocytopenia. However, it remains unclear, whether TPO mimetics influence the increase of blast cells and therefore to premature progression to AML. To evaluate the efficacy and safety of thrombopoietin (TPO) mimetics for patients with MDS. We searched for randomised controlled trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 2000 to August 2017), trials registries (ISRCTN, EU clinical trials register and clinicaltrials.gov) and conference proceedings. We did not apply any language restrictions. Two review authors independently screened search results, disagreements were solved by discussion. We included randomised controlled trials comparing TPO mimetics with placebo, no further treatment or another TPO mimetic in patients with MDS of all risk groups, without gender, age or ethnicity restrictions. Additional chemotherapeutic treatment had to be equal in both arms. Two review authors independently extracted data and assessed the quality of trials, disagreements were resolved by discussion. Risk ratio (RR) was used to analyse mortality during study, transformation to AML, incidence of bleeding events, transfusion requirement, all adverse events, adverse events >= grade 3, serious adverse events and platelet response. Overall survival (OS) and progression-free survival (PFS) have been extracted as hazard ratios, but

  3. Antibody mimetics: promising complementary agents to animal-sourced antibodies.

    PubMed

    Baloch, Abdul Rasheed; Baloch, Abdul Wahid; Sutton, Brian J; Zhang, Xiaoying

    2016-01-01

    Despite their wide use as therapeutic, diagnostic and detection agents, the limitations of polyclonal and monoclonal antibodies have inspired scientists to design the next generation biomedical agents, so-called antibody mimetics that offer many advantages over conventional antibodies. Antibody mimetics can be constructed by protein-directed evolution or fusion of complementarity-determining regions through intervening framework regions. Substantial progress in exploiting human, butterfly (Pieris brassicae) and bacterial systems to design and select mimetics using display technologies has been made in the past 10 years, and one of these mimetics [Kalbitor® (Dyax)] has made its way to market. Many challenges lie ahead to develop mimetics for various biomedical applications, especially those for which conventional antibodies are ineffective, and this review describes the current characteristics, construction and applications of antibody mimetics compared to animal-sourced antibodies. The possible limitations of mimetics and future perspectives are also discussed.

  4. Wood mimetic hydrogel beads for enzyme immobilization.

    PubMed

    Park, Saerom; Kim, Sung Hee; Won, Keehoon; Choi, Joon Weon; Kim, Yong Hwan; Kim, Hyung Joo; Yang, Yung-Hun; Lee, Sang Hyun

    2015-01-22

    Wood component-based composite hydrogels have potential applications in biomedical fields owing to their low cost, biodegradability, and biocompatibility. The controllable properties of wood mimetic composites containing three major wood components are useful for enzyme immobilization. Here, lipase from Candida rugosa was entrapped in wood mimetic beads containing cellulose, xylan, and lignin by dissolving wood components with lipase in [Emim][Ac], followed by reconstitution. Lipase entrapped in cellulose/xylan/lignin beads in a 5:3:2 ratio showed the highest activity; this ratio is very similar to that in natural wood. The lipase entrapped in various wood mimetic beads showed increased thermal and pH stability. The half-life times of lipase entrapped in cellulose/alkali lignin hydrogel were 31- and 82-times higher than those of free lipase during incubation under denaturing conditions of high temperature and low pH, respectively. Owing to their biocompatibility, biodegradability, and controllable properties, wood mimetic hydrogel beads can be used to immobilize various enzymes for applications in the biomedical, bioelectronic, and biocatalytic fields. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. NEC violation in mimetic cosmology revisited

    SciTech Connect

    Ijjas, Anna; Ripley, Justin; Steinhardt, Paul J.

    2016-06-28

    In the context of Einstein gravity, if the null energy condition (NEC) is satisfied, the energy density in expanding space–times always decreases while in contracting space–times the energy density grows and the universe eventually collapses into a singularity. In particular, no non-singular bounce is possible. It is, though, an open question if this energy condition can be violated in a controlled way, i.e., without introducing pathologies, such as unstable negative-energy states or an imaginary speed of sound. In this letter, we will re-examine the claim that the recently proposed mimetic scenario can violate the NEC without pathologies. We show thatmore » mimetic cosmology is prone to gradient instabilities even in cases when the NEC is satisfied (except for trivial examples). Most interestingly, the source of the instability is always the Einstein–Hilbert term in the action. The matter stress-energy component does not contribute spatial gradient terms but instead makes the problematic curvature modes dynamical. Finally, we also show that mimetic cosmology can be understood as a singular limit of known, well-behaved theories involving higher-derivative kinetic terms and discuss ways of removing the instability.« less

  6. Mechanisms Involved in Thromboxane A2-induced Vasoconstriction of Rat Intracavernous Small Penile Arteries.

    PubMed

    Grann, Martin; Comerma-Steffensen, Simon; Arcanjo, Daniel D R; Simonsen, Ulf

    2016-10-01

    Diabetes is associated with erectile dysfunction and with hypercontractility in erectile tissue and this is in part ascribed to increased formation of thromboxane. Rho kinase (ROCK) is a key regulator of calcium sensitization and contraction in vascular smooth muscle. This study investigated the role of calcium and ROCK in contraction evoked by activation of the thromboxane receptors. Rat intracavernous penile arteries were mounted for isometric tension and intracellular calcium ([Ca 2+ ] i ) recording and corpus cavernosum for measurements of MYPT1 phosphorylation. In penile arteries, U46619 by activation of thromboxane receptors concentration dependently increased calcium and contraction. U46619-induced calcium influx was blocked by nifedipine, a blocker of L-type calcium channels, and by 2-aminoethoxydiphenyl borate, a blocker of transient receptor potential (TRP) channels. Inhibitors of ROCK, Y27632 and glycyl-H1152P, concentration dependently reduced U46619-induced contraction, but only Y27632 reduced [Ca 2+ ] i levels in the penile arteries activated with either high extracellular potassium or U46619. MYPT-Thr 850 phosphorylation in corpus cavernous strips was increased in response to U46619 through activation of TP receptors and was found to be a direct result of phosphorylation by ROCK. Y27632 induced less relaxation in mesenteric arteries, H1152P induced equipotent relaxations, and a protein kinase C inhibitor, Ro-318220, failed to relax intracavernous penile arteries, but induced full relaxation in rat mesenteric arteries. Our findings suggest that U46619 contraction depends on Ca 2+ influx through L-type and TRP channels, and ROCK-dependent mechanisms in penile arteries. Inhibition of the ROCK pathway is a potential approach for the treatment of erectile dysfunction associated with hypertension and diabetes. © 2015 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  7. Progress of Mimetic Enzymes and Their Applications in Chemical Sensors.

    PubMed

    Yang, Bin; Li, Jianping; Deng, Huan; Zhang, Lianming

    2016-11-01

    The need to develop innovative and reformative approaches to synthesize chemical sensors has increased in recent years because of demands for selectivity, stability, and reproducibility. Mimetic enzymes provide an efficient and convenient method for chemical sensors. This review summarizes the application of mimetic enzymes in chemical sensors. Mimetic enzymes can be classified into five categories: hydrolases, oxidoreductases, transferases, isomerases, and induced enzymes. Potential and recent applications of mimetic enzymes in chemical sensors are reviewed in detail, and the outlook of profound development has been illustrated.

  8. Direct couplings of mimetic dark matter and their cosmological effects

    NASA Astrophysics Data System (ADS)

    Shen, Liuyuan; Mou, Yicen; Zheng, Yunlong; Li, Mingzhe

    2018-01-01

    The original mimetic model was proposed to take the role of dark matter. In this paper we consider possible direct interactions of mimetic dark matter with other matter in the universe, especially standard model particles such as baryons and photons. By imposing shift symmetry, the mimetic dark matter field can only have derivative couplings. We discuss the possibilities of generating baryon number asymmetry and cosmic birefringence in the universe based on the derivative couplings of mimetic dark matter to baryons and photons. Supported by NSFC (11422543, 11653002)

  9. Effect of mimetic CDK9 inhibitors on HIV-1 activated transcription

    PubMed Central

    Van Duyne, Rachel; Guendel, Irene; Jaworski, Elizabeth; Sampey, Gavin; Klase, Zachary; Chen, Hao; Zeng, Chen; Kovalskyy, Dmytro; el Kouni, Mahmoud H.; Lepene, Benjamin; Patanarut, Alexis; Nekhai, Sergei; Price, David H.; Kashanchi, Fatah

    2013-01-01

    Potent antiretroviral therapy (ART) has transformed HIV-1 infection into a chronic manageable disease; however drug resistance remains a common problem that limits the effectiveness and clinical benefits of this type of treatment. The discovery of viral reservoirs in the body, in which HIV-1 may persist, has helped to explain why therapeutic eradication of HIV-1 has proved so difficult. In the current study we utilized a combination of structure based analysis of Cyclin/CDK complexes with our previously published Tat peptide derivatives. We modeled the Tat peptide inhibitors with CDKs and found a particular pocket which showed the most stable binding site (Cavity 1) using in silico analysis. Furthermore, we were able to find peptide mimetics that bound to similar regions using in silico searches of a chemical library, followed by cell based biological assays. Using these methods we obtained the first generation mimetic drugs and tested these compounds on HIV-1 LTR activated transcription. Using biological assays followed by similar in silico analysis to find a 2nd generation drugs resembling the original mimetic, we found the new targets of Cavity 1 and Cavity 2 regions on CDK9. We examined the 2nd generation mimetic against various viral isolates, and observed a generalized suppression of most HIV-1 isolates. Finally, the drug inhibited viral replication in humanized mouse models of Rag2-/-γc-/- with no toxicity to the animals at tested concentrations. Our results suggest that it may be possible to model peptide inhibitors into available crystal structures and further find drug mimetics using in silico analysis. PMID:23247501

  10. Bound to the Mimetic or the Transformative?: Considering Other Possibilities

    ERIC Educational Resources Information Center

    Frank, Jeff

    2017-01-01

    Philip Jackson's "The Mimetic and the Transformative: Alternative Outlooks on Teaching" is widely read both inside and outside of philosophy of education circles and courses, and is best known for sketching out the long-standing difference between the mimetic and transformative traditions in teaching. In this paper, I argue that we need…

  11. Black hole solutions in mimetic Born-Infeld gravity

    NASA Astrophysics Data System (ADS)

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-01

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite.

  12. Black hole solutions in mimetic Born-Infeld gravity

    SciTech Connect

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-23

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. Here, we find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularitymore » is found to be infinite.« less

  13. Black hole solutions in mimetic Born-Infeld gravity.

    PubMed

    Chen, Che-Yu; Bouhmadi-López, Mariam; Chen, Pisin

    2018-01-01

    The vacuum, static, and spherically symmetric solutions in the mimetic Born-Infeld gravity are studied. The mimetic Born-Infeld gravity is a reformulation of the Eddington-inspired-Born-Infeld (EiBI) model under the mimetic approach. Due to the mimetic field, the theory contains non-trivial vacuum solutions different from those in Einstein gravity. We find that with the existence of the mimetic field, the spacelike singularity inside a Schwarzschild black hole could be altered to a lightlike singularity, even though the curvature invariants still diverge at the singularity. Furthermore, in this case, the maximal proper time for a timelike radially-infalling observer to reach the singularity is found to be infinite.

  14. Exercise Mimetics: Impact on Health and Performance.

    PubMed

    Fan, Weiwei; Evans, Ronald M

    2017-02-07

    The global epidemic of obesity and its associated chronic diseases is largely attributed to an imbalance between caloric intake and energy expenditure. While physical exercise remains the best solution, the development of muscle-targeted "exercise mimetics" may soon provide a pharmaceutical alternative to battle an increasingly sedentary lifestyle. At the same time, these advances are fueling a raging debate on their escalating use as performance-enhancing drugs in high-profile competitions such as the Olympics. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Exercise, fasting, and mimetics: toward beneficial combinations?

    PubMed

    Jaspers, Richard T; Zillikens, M Carola; Friesema, Edith C H; delli Paoli, Giuseppe; Bloch, Wilhelm; Uitterlinden, André G; Goglia, Fernando; Lanni, Antonia; de Lange, Pieter

    2017-01-01

    Obesity and type 2 diabetes are associated disorders that involve a multiplicity of tissues. Both fasting and physical exercise are known to counteract dyslipidemia/hyperglycemia. Skeletal muscle plays a key role in the control of blood glucose levels, and the metabolic changes and related signaling pathways in skeletal muscle induced by fasting overlap with those induced by exercise. The reduction of fat disposal has been shown to extend to the liver and to white and brown adipose tissue and to involve an increase in their metabolic activities. In recent years signal transduction pathways related to exercise and fasting/food withdrawal in muscle have been intensively studied, both in animals and in humans. Combining fasting/food withdrawal with exercise in animals as well as in humans causes changes unlike those seen during fasting/food withdrawal or exercise alone, which favor repair of muscle over autophagy. In addition, compounds that mimic exercise have been studied in combination with exercise or fasting/food withdrawal. This review addresses our current knowledge of the mechanisms that underlie the individual and combined effects of fasting/food withdrawal, endurance or resistance exercise, and their mimetics, in muscle vs other organs in rodents and humans, and highlights which combinations may improve metabolic disorders.-Jaspers, R. T., Zillikens, M. C., Friesema, E. C. H., delli Paoli, G., Bloch, W., Uitterlinden, A. G., Goglia, F., Lanni, A., de Lange, P. Exercise, fasting, and mimetics: toward beneficial combinations. © FASEB.

  16. Pharmacological and histological examinations of regional differences of guinea-pig lung: a role of pleural surface smooth muscle in lung strip contraction.

    PubMed Central

    Wong, W. S.; Bloomquist, S. L.; Bendele, A. M.; Fleisch, J. H.

    1992-01-01

    1. Parenchymal lung strip preparations have been widely used as an in vitro model of peripheral airway smooth muscle. The present study examined functional responses of 4 consecutive guinea-pig lung parenchymal strips isolated from the central region (segment 1) to the distal edge (segment 4) of the lower lung lobe. The middle two segments were designated as segments 2 and 3. 2. Lung segments 1 and 4 exhibited significantly greater contraction than the other 2 segments to KCl when responses were expressed as mg force per mg tissue weight. Contractile responses to bronchospastic agents including histamine, carbachol, endothelin-1, leukotrienes (LT) B4 and D4, and the thromboxane A2-mimetic U46619 demonstrated no significant difference in EC50 values among the 4 lung segments. 3. Contractile responses of segments 1 and 4 to antigen-challenge (ovalbumin), ionophore A23187 and substance P were significantly greater than the other 2 segments with respect to either sensitivity or maximum responsiveness. 4. U46619-induced contractions of the 4 lung segments were relaxed in similar manner by papaverine and theophylline up to 100%, salbutamol up to 80%, and sodium nitroprusside by only 20%. In contrast, sodium nitroprusside markedly reversed U46619-induced contraction of pulmonary arterial rings and bronchial rings. 5. Histological studies identified 2-4 layers of smooth muscle cells underlying the lung pleural surface. Mast cells were prominent in this area. Moreover, morphometric studies showed that segment 4 possessed the least amount of smooth muscle structures from bronchial/bronchiolar wall and vasculatures as compared to the other 3 segments, and a significant difference in this respect was evident between segment 1 and segment 4.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 6 PMID:1378341

  17. A spectral mimetic least-squares method

    DOE PAGES

    Bochev, Pavel; Gerritsma, Marc

    2014-09-01

    We present a spectral mimetic least-squares method for a model diffusion–reaction problem, which preserves key conservation properties of the continuum problem. Casting the model problem into a first-order system for two scalar and two vector variables shifts material properties from the differential equations to a pair of constitutive relations. We also use this system to motivate a new least-squares functional involving all four fields and show that its minimizer satisfies the differential equations exactly. Discretization of the four-field least-squares functional by spectral spaces compatible with the differential operators leads to a least-squares method in which the differential equations are alsomore » satisfied exactly. Additionally, the latter are reduced to purely topological relationships for the degrees of freedom that can be satisfied without reference to basis functions. Furthermore, numerical experiments confirm the spectral accuracy of the method and its local conservation.« less

  18. Nuclear receptors and AMPK: can exercise mimetics cure diabetes?

    PubMed

    Wall, Christopher E; Yu, Ruth T; Atkins, Anne R; Downes, Michael; Evans, Ronald M

    2016-07-01

    Endurance exercise can lead to systemic improvements in insulin sensitivity and metabolic homeostasis, and is an effective approach to combat metabolic diseases. Pharmacological compounds that recapitulate the beneficial effects of exercise, also known as 'exercise mimetics', have the potential to improve disease symptoms of metabolic syndrome. These drugs, which can increase energy expenditure, suppress hepatic gluconeogenesis, and induce insulin sensitization, have accordingly been highly scrutinized for their utility in treating metabolic diseases including diabetes. Nevertheless, the identity of an efficacious exercise mimetic still remains elusive. In this review, we highlight several nuclear receptors and cofactors that are putative molecular targets for exercise mimetics, and review recent studies that provide advancements in our mechanistic understanding of how exercise mimetics exert their beneficial effects. We also discuss evidence from clinical trials using these compounds in human subjects to evaluate their efficacy in treating diabetes. © 2016 Society for Endocrinology.

  19. Smac Mimetics to Therapeutically Target IAP Proteins in Cancer.

    PubMed

    Fulda, S

    2017-01-01

    Inhibitor of Apoptosis (IAP) proteins are overexpressed in a variety of human cancers. Therefore, they are considered as promising targets for the design of therapeutic strategies. Smac mimetics mimic the endogenous mitochondrial protein Smac that antagonizes IAP proteins upon its release into the cytosol. Multiple preclinical studies have documented the ability of Smac mimetics to either directly induce cell death of cancer cells or to prime them to agents that trigger cell death. At present, several Smac mimetics are being evaluated in early clinical trials. The current review provides an overview on the potential of Smac mimetics as cancer therapeutics to target IAP proteins for cancer therapy. © 2017 Elsevier Inc. All rights reserved.

  20. Promises and Challenges of Smac Mimetics as Cancer Therapeutics.

    PubMed

    Fulda, Simone

    2015-11-15

    Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics. ©2015 American Association for Cancer Research.

  1. Crossmodal Modulation of Spatial Localization by Mimetic Words

    PubMed Central

    Yamada, Yuki; Miura, Kayo

    2016-01-01

    The present study investigated whether aurally presented mimetic words affect the judgment of the final position of a moving object. In Experiment 1, horizontal apparent motion of a visual target was presented, and an auditory mimetic word of “byun” (representing rapid forward motion), “pitari” (representing stop of motion), or “nisahi” (nonsense syllable) was presented via headphones. Observers were asked to judge which of two test stimuli was horizontally aligned with the target. The results showed that forward displacement in the “pitari” condition was significantly smaller than in the “byun” and “nisahi” conditions. However, when non-mimetic but meaningful words were presented (Experiment 2), this effect did not occur. Our findings suggest that the mimetic words, especially that meaning stop of motion, affect spatial localization by means of mental imagery regarding “stop” established by the phonological information of the word. PMID:27994845

  2. Towards natural mimetics of metformin and rapamycin.

    PubMed

    Aliper, Alexander; Jellen, Leslie; Cortese, Franco; Artemov, Artem; Karpinsky-Semper, Darla; Moskalev, Alexey; Swick, Andrew G; Zhavoronkov, Alex

    2017-11-15

    Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals-safer, naturally-occurring compounds-that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors.

  3. [Insulin-mimetic property of vanadium compounds].

    PubMed

    Korbecki, Jan; Baranowska-Bosiacka, Irena; Gutowska, Izabela; Chlubek, Dariusz

    Vanadium is a transition metal which creates a number of inorganic and organic derivatives with various organic substances. Some of these compounds have pharmaceutical significance, e.g. vanadyl cation, vanadate and bis(maltolato) oxovanadium(IV). Vanadium compounds are competence inhibitors of protein tyrosine phosphatases (PTP). They have anti-tumor properties, capable of inhibiting cell proliferation at the concentrations of several micromoles. They also display insulin-mimetic and hypoglycemic properties. As they can increase the activity of the insulin-like growth factor I receptor, they stimulate glycogen synthesis, increase the number of GLUT-4 transporters in the cell membrane and impair gluconeogenesis. In addition to their effects on sugar metabolism, vanadium compounds increase the synthesis of fatty acids, reducing the concentration of glucose in the blood. Thanks to their mitotic properties, low concentrations of vanadium compounds are also able to induce β cell regeneration. Clinical tests have shown that vanadium compounds may be used as antidiabetic drugs with low toxicity. However, the range of therapeutic concentrations is very narrow; at concentrations as low a several micromoles vanadium compounds inhibit cell proliferation and cause apoptosis, necrosis and inflammation.

  4. Towards natural mimetics of metformin and rapamycin

    PubMed Central

    Aliper, Alexander; Jellen, Leslie; Cortese, Franco; Artemov, Artem; Karpinsky-Semper, Darla; Moskalev, Alexey; Swick, Andrew G.; Zhavoronkov, Alex

    2017-01-01

    Aging is now at the forefront of major challenges faced globally, creating an immediate need for safe, widescale interventions to reduce the burden of chronic disease and extend human healthspan. Metformin and rapamycin are two FDA-approved mTOR inhibitors proposed for this purpose, exhibiting significant anti-cancer and anti-aging properties beyond their current clinical applications. However, each faces issues with approval for off-label, prophylactic use due to adverse effects. Here, we initiate an effort to identify nutraceuticals—safer, naturally-occurring compounds—that mimic the anti-aging effects of metformin and rapamycin without adverse effects. We applied several bioinformatic approaches and deep learning methods to the Library of Integrated Network-based Cellular Signatures (LINCS) dataset to map the gene- and pathway-level signatures of metformin and rapamycin and screen for matches among over 800 natural compounds. We then predicted the safety of each compound with an ensemble of deep neural network classifiers. The analysis revealed many novel candidate metformin and rapamycin mimetics, including allantoin and ginsenoside (metformin), epigallocatechin gallate and isoliquiritigenin (rapamycin), and withaferin A (both). Four relatively unexplored compounds also scored well with rapamycin. This work revealed promising candidates for future experimental validation while demonstrating the applications of powerful screening methods for this and similar endeavors. PMID:29165314

  5. Energy restriction and potential energy restriction mimetics.

    PubMed

    Nikolai, Sibylle; Pallauf, Kathrin; Huebbe, Patricia; Rimbach, Gerald

    2015-12-01

    Energy restriction (ER; also known as caloric restriction) is the only nutritional intervention that has repeatedly been shown to increase lifespan in model organisms and may delay ageing in humans. In the present review we discuss current scientific literature on ER and its molecular, metabolic and hormonal effects. Moreover, criteria for the classification of substances that might induce positive ER-like changes without having to reduce energy intake are summarised. Additionally, the putative ER mimetics (ERM) 2-deoxy-d-glucose, metformin, rapamycin, resveratrol, spermidine and lipoic acid and their suggested molecular targets are discussed. While there are reports on these ERM candidates that describe lifespan extension in model organisms, data on longevity-inducing effects in higher organisms such as mice remain controversial or are missing. Furthermore, some of these candidates produce detrimental side effects such as immunosuppression or lactic acidosis, or have not been tested for safety in long-term studies. Up to now, there are no known ERM that could be recommended without limitations for use in humans.

  6. Dispersal of mimetic seeds of three species of Ormosia (Leguminosae)

    USGS Publications Warehouse

    Foster, M.S.; DeLay, L.S.

    1998-01-01

    Seeds with 'imitation arils' appear wholly or partially covered by pulp or aril but actually carry no fleshy material. The mimetic seed hypothesis to explain this phenomenon proposes a parasitic relationship in which birds are deceived into dispersing seeds that resemble bird-dispersed fruits, without receiving a nutrient reward. The hard-seed for grit hypothesis proposes a mutualistic relationship in which large, terrestrial birds swallow the exceptionally hard 'mimetic' seeds as grit for grinding the softer seeds on which they feed. They defecate, dispersing the seeds, and abrade the seed surface, enhancing germination. Any fruit mimicry is incidental. Fruiting trees of Ormosia spp. (Leguminosae: Papilionoideae) were observed to ascertain mechanisms of seed dispersal and the role of seemingly mimetic characteristics of the seeds in that dispersal. Seed predation and seed germination were also examined. Ormosia isthamensis and O. macrocalyx (but not O. bopiensis) deceived arboreally-foraging frugivorous birds into taking their mimetic seeds, although rates of seed dispersal were low. These results are consistent with the mimetic seed hypothesis. On the other hand, the rates of disappearance of seeds from the ground under the Ormosia trees, hardness of the seeds, and enhancement of germination with the abrasion of the seed coat are all consistent with the hard-seed for grit hypothesis.

  7. Tunicate-mimetic nanofibrous hydrogel adhesive with improved wet adhesion.

    PubMed

    Oh, Dongyeop X; Kim, Sangsik; Lee, Dohoon; Hwang, Dong Soo

    2015-07-01

    The main impediment to medical application of biomaterial-based adhesives is their poor wet adhesion strength due to hydration-induced softening and dissolution. To solve this problem, we mimicked the wound healing process found in tunicates, which use a nanofiber structure and pyrogallol group to heal any damage on its tunic under sea water. We fabricated a tunicate-mimetic hydrogel adhesive based on a chitin nanofiber/gallic acid (a pyrogallol acid) composite. The pyrogallol group-mediated cross-linking and the nanofibrous structures improved the dissolution resistance and cohesion strength of the hydrogel compared to the amorphous polymeric hydrogels in wet condition. The tunicate-mimetic adhesives showed higher adhesion strength between fully hydrated skin tissues than did fibrin glue and mussel-mimetic adhesives. The tunicate mimetic hydrogels were produced at low cost from recyclable and abundant raw materials. This tunicate-mimetic adhesive system is an example of how natural materials can be engineered for biomedical applications. Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  8. Extended mimetic gravity: Hamiltonian analysis and gradient instabilities

    NASA Astrophysics Data System (ADS)

    Takahashi, Kazufumi; Kobayashi, Tsutomu

    2017-11-01

    We propose a novel class of degenerate higher-order scalar-tensor theories as an extension of mimetic gravity. By performing a noninvertible conformal transformation on "seed" scalar-tensor theories which may be nondegenerate, we can generate a large class of theories with at most three physical degrees of freedom. We identify a general seed theory for which this is possible. Cosmological perturbations in these extended mimetic theories are also studied. It is shown that either of tensor or scalar perturbations is plagued with gradient instabilities, except for a special case where the scalar perturbations are presumably strongly coupled, or otherwise there appear ghost instabilities.

  9. Energy conditions in mimetic-f(R) gravity

    NASA Astrophysics Data System (ADS)

    Haghani, Zahra; Shiravand, Maryam; Shahidi, Shahab

    The energy conditions of mimetic-f(R) gravity theory is analyzed. We will obtain the parameter space of the theory in some special forms of f(R) in which the self-acceleration is allowed. In this sense, the parameter space is obtained in a way that it violates the strong energy condition while satisfying the weak, null and dominant energy conditions. We will also consider the condition that the Dolgov-Kawasaki instability is avoided. This condition will be further imposed in the parameter space of the theory. We will show that the parameter space of the mimetic-f(R) gravity is larger than f(R) gravity theory.

  10. Simple mimetics of a nuclear localization signal (NLS).

    PubMed

    Park, Seung Bum; Ho, Thai H; Reedy, Brian M; Connolly, Michael D; Standaert, Robert F

    2003-07-10

    [reaction: see text] Molecular modeling was used to design mimetics of the HIV-1 matrix protein nuclear localization signal (NLS) in which a scaffold of two resorcinol units joined by a diamide linker presents 3-aminopropyl ethers in place of lysine side chains. Prospective mimetics with linkers of 6, 8, 10, or 12 atoms were synthesized and compared in a competition assay for binding to the nuclear import receptor subunit karyopherin alpha, showing the 10-atom linker to be best and shorter ones ineffective.

  11. The IAP Protein Family, SMAC Mimetics and Cancer Treatment.

    PubMed

    Philchenkov, Alex; Miura, Koh

    2016-01-01

    Since the acquired resistance of cells to apoptosis is one of the major hallmarks of cancer, the endogenous inhibitors of apoptosis can be regarded as promising targets in the design of anticancer therapeutics. In addition to their antiapoptotic activity, inhibitor of apoptosis proteins (IAPs) are able to regulate numerous other cell functions, including proliferation, differentiation, and migration, as well as proinflammatory and immune responses. Study of the IAP family as target molecules in targeted therapies has recently focused on SMAC mimetics as synthetic IAP antagonists that have been under development as promising therapeutics. To overview the background of IAP proteins and to focus on the development of SMAC mimetics, the present review first looks at the mechanisms of IAP proteins' antiapoptotic activities and those for controlling those activities; then the SMAC mimetics, including birinapant, LCL161, and DEBIO1143/AT-406, and their clinical trials are introduced. To further clarify the processes to exert the efficacies of SMAC mimetics, it is necessary to determine therapeutic biomarkers that predict and assess them, which may include caspases and factors in the TNFα pathway.

  12. Mimetics of Hormetic Agents: Stress-Resistance Triggers

    PubMed Central

    Sonneborn, Joan Smith

    2010-01-01

    Mimetics of hormetic agents offer a novel approach to adjust dose to minimize the risk of toxic response, and maximize the benefit of induction of at least partial physiological conditioning. Nature selected and preserved those organisms and triggers that promote tolerance to stress. The induced tolerance can serve to resist that challenge and can repair previous age, disease, and trauma damage as well to provide a more youthful response to other stresses. The associated physiological conditioning may include youthful restoration of DNA repair, resistance to oxidizing pollutants, protein structure and function repair, improved immunity, tissue remodeling, adjustments in central and peripheral nervous systems, and altered metabolism. By elucidating common pathways activated by hormetic agent’s mimetics, new strategies for intervention in aging, disease, and trauma emerge. Intervention potential in cancer, diabetes, age-related diseases, infectious diseases, cardiovascular diseases, and Alzheimer’s disease are possible. Some hormetic mimetics exist in pathways in primitive organisms and are active or latent in humans. Peptides, oligonucleotides, and hormones are among the mimetics that activate latent resistance to radiation, physical endurance, strength, and immunity to physiological condition tolerance to stress. Co-activators may be required for expression of the desired physiological conditioning health and rejuvenation benefits. PMID:20221297

  13. Cell outer membrane mimetic chitosan nanoparticles: preparation, characterization and cytotoxicity.

    PubMed

    Zhao, Jing; Liang, Fei; Kong, Lingheng; Zheng, Lina; Fan, Tao

    2015-01-01

    A negatively charged copolymer poly (MPC-co-AMPS) of 2-methacryloyloxyethyl phosphorylcholine (MPC) and 2-acrylamide-2-methyl propane sulfonic acid (AMPS) was designed and synthesized. Chitosan nanoparticles with cell outer membrane mimetic structure were prepared by electrostatic interaction between the sulfonic acid groups of poly (MPC-co-AMPS) and the protonated amino groups of chitosan. Effects of factors on influencing the particle size, distribution, and stability were investigated. The experimental results showed that cell membrane mimetic chitosan nanoparticles with controllable and homogeneous size ranged from 100 to 300 nm were prepared at the concentration of 0.1-2.0 mg/mL and the charge ratio of 0.5-1.1. Chitosan nanoparticles prepared can exist stably for more than 45 days when placed at 4 °C and pH < 7.5. The cytotoxicity of the chitosan nanoparticles reduced significantly after surface modification with cell membrane mimetic structure, meeting the basic requirements of biomedical materials. The results suggest cell membrane mimetic chitosan nanoparticles prepared with polyanion and polycation obtain good biological compatibility and immune stealth ability, which has important academic significance and great application prospects.

  14. Bio-Mimetic Sensors Based on Molecularly Imprinted Membranes

    PubMed Central

    Algieri, Catia; Drioli, Enrico; Guzzo, Laura; Donato, Laura

    2014-01-01

    An important challenge for scientific research is the production of artificial systems able to mimic the recognition mechanisms occurring at the molecular level in living systems. A valid contribution in this direction resulted from the development of molecular imprinting. By means of this technology, selective molecular recognition sites are introduced in a polymer, thus conferring it bio-mimetic properties. The potential applications of these systems include affinity separations, medical diagnostics, drug delivery, catalysis, etc. Recently, bio-sensing systems using molecularly imprinted membranes, a special form of imprinted polymers, have received the attention of scientists in various fields. In these systems imprinted membranes are used as bio-mimetic recognition elements which are integrated with a transducer component. The direct and rapid determination of an interaction between the recognition element and the target analyte (template) was an encouraging factor for the development of such systems as alternatives to traditional bio-assay methods. Due to their high stability, sensitivity and specificity, bio-mimetic sensors-based membranes are used for environmental, food, and clinical uses. This review deals with the development of molecularly imprinted polymers and their different preparation methods. Referring to the last decades, the application of these membranes as bio-mimetic sensor devices will be also reported. PMID:25196110

  15. Minimalist Antibodies and Mimetics: An Update and Recent Applications.

    PubMed

    Bruce, Virginia J; Ta, Angeline N; McNaughton, Brian R

    2016-10-17

    The immune system utilizes antibodies to recognize foreign or disease-relevant receptors, initiating an immune response to destroy unwelcomed guests. Because researchers can evolve antibodies to bind virtually any target, it is perhaps unsurprising that these reagents, and their small-molecule conjugates, are used extensively in clinical and basic research environments. However, virtues of antibodies are countered by significant challenges. Foremost among these is the need for expression in mammalian cells (largely due to often necessary post-translational modifications). In response to these challenges, researchers have developed an array of minimalist antibodies and mimetics, which are smaller, more stable, simpler to express in Escherichia coli, and amendable to laboratory evolution and protein engineering. Here we describe these scaffolds and discuss recent applications of minimalist antibodies and mimetics. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  16. Molecular pathways: targeting death receptors and smac mimetics.

    PubMed

    Fulda, Simone

    2014-08-01

    Inhibitor of apoptosis (IAP) proteins are overexpressed in multiple human malignancies, an event that is associated with poor prognosis and treatment resistance. Therefore, IAP proteins represent relevant targets for therapeutic intervention. Second mitochondrial activator of caspases (Smac) is a mitochondrial protein that is released into the cytosol upon the induction of programmed cell death and promotes apoptosis by neutralizing IAP proteins. On the basis of this property, a variety of small-molecule inhibitors have been developed that mimic the binding domain of the native Smac protein to IAP proteins. Evaluation of these Smac mimetics in preclinical studies revealed that they particularly synergize together with agents that trigger the death receptor pathway of apoptosis. Such combinations might therefore be of special interest for being included in the ongoing evaluation of Smac mimetics in early clinical trials. ©2014 American Association for Cancer Research.

  17. Salicylamide and salicylglycine oxidovanadium complexes with insulin-mimetic properties.

    PubMed

    Nilsson, Jessica; Shteinman, Albert A; Degerman, Eva; Enyedy, Eva A; Kiss, Tamás; Behrens, Ulrich; Rehder, Dieter; Nordlander, Ebbe

    2011-12-01

    Reaction of N-(2-hydroxybenzyl)-N-(2-picolyl) glycine (H(2)papy) with VOSO(4) in water gives the oxidovanadium(V) oxido-bridged dimer [{(papy)(VO)}(2) μ-O)] (1). Similarly, reaction of N-(2-hydroxybenzyl) glycine (H(2)glysal) with VOSO(4) gives [(glysal)VO(H(2)O)] (2) and reaction of salicylamide (Hsalam) with VOSO(4) in methanol gives [(salam)(2)VO] (3). The crystal structure of the oxido-bridged complex 1 is reported. The insulin-mimetic activity of all three complexes was evaluated with respect to their ability to phosphorylate protein kinase B (PKB). The speciations of complexes 1 and 2 were studied over the pH range 2-10. Complex 1 shows greater stability over the whole pH range but only 2 and 3 exhibit an insulin-mimetic effect. Copyright © 2011 Elsevier Inc. All rights reserved.

  18. Imperfect Batesian mimicry and the conspicuousness costs of mimetic resemblance.

    PubMed

    Speed, Michael P; Ruxton, Graeme D

    2010-07-01

    We apply signal detection methodology to make predictions about the evolution of Batesian mimicry. Our approach is novel in three ways. First, we applied a deterministic evolutionary modeling system that allows a large number of alternative mimetic morphs to coexist and compete. Second, we considered that there may be natural boundaries to phenotypic expression. Finally, we allowed increasing conspicuousness to impose an increasing detection cost on mimics. In some instances, the model predicts widespread variation in mimetic forms at evolutionary stability. In other situations, rather than a polymorphism the model predicts dimorphisms in which some prey were maximally cryptic and had minimal resemblance to the model, whereas many others were more conspicuous than the model. The biological implications of these results, particularly for our understanding of imperfect mimicry, are discussed.

  19. Fabrication of hierarchical feather-mimetic polymer nanofibres

    NASA Astrophysics Data System (ADS)

    Ouyang, Shenshen; Wang, Tao; Zhong, Longgang; Peng, Meiling; Yao, Juming; Wang, Sheng

    2018-01-01

    In this study, hierarchically feather-mimetic structures formed of poly(m-phenylene isophthalamide) (PMIA) nanofibres were prepared by electrospinning and subsequent crystallisation for superwettability applications. X-ray diffraction measurementsand scanning electron microscopy show that a feather-mimetic structure of crystallised nanoflakes was formed following a hydrothermal treatment process. The nanoflakes formed a nanosized fine texture on top of a coarser-textured membrane, which greatly improved the membrane roughness and yielded a hierarchical topography. After fluorination, the membrane exhibited superamphiphobicity, with surface contact angles of 151° and 136° for water and hexadecane, respectively. The method provides new insight for the design and development of functional bionic membranes based on PMIA.

  20. Primordial cosmology in mimetic born-infeld gravity

    SciTech Connect

    Bouhmadi-Lopez, Mariam; Chen, Che -Yu; Chen, Pisin

    2017-11-29

    Here, the Eddington-inspired-Born-Infeld (EiBI) model is reformulated within the mimetic approach. In the presence of a mimetic field, the model contains non-trivial vacuum solutions which could be free of spacetime singularity because of the Born-Infeld nature of the theory. We study a realistic primordial vacuum universe and prove the existence of regular solutions, such as primordial inflationary solutions of de Sitter type or bouncing solutions. Besides, the linear instabilities present in the EiBI model are found to be avoidable for some interesting bouncing solutions in which the physical metric as well as the auxiliary metric are regular at the backgroundmore » level.« less

  1. Beyond dRGT as mimetic massive gravity

    NASA Astrophysics Data System (ADS)

    Golovnev, Alexey

    2018-04-01

    An interesting proposal has recently been made to extend massive gravity models beyond dRGT by a disformal transformation of the metric. In this Letter we want to note that it can be viewed as a mimetic extension of dRGT gravity which enormously simplifies the Hamiltonian analysis. In particular, pure gravity sector is equivalent to the usual dRGT gravity coupled to a constrained scalar field. And we also give some comments about possible matter couplings.

  2. On (in)stabilities of perturbations in mimetic models with higher derivatives

    SciTech Connect

    Zheng, Yunlong; Shen, Liuyuan; Mou, Yicen

    2017-08-01

    Usually when applying the mimetic model to the early universe, higher derivative terms are needed to promote the mimetic field to be dynamical. However such models suffer from the ghost and/or the gradient instabilities and simple extensions cannot cure this pathology. We point out in this paper that it is possible to overcome this difficulty by considering the direct couplings of the higher derivatives of the mimetic field to the curvature of the spacetime.

  3. Insulin Reverses D-Glucose–Increased Nitric Oxide and Reactive Oxygen Species Generation in Human Umbilical Vein Endothelial Cells

    PubMed Central

    González, Marcelo; Rojas, Susana; Avila, Pía; Cabrera, Lissette; Villalobos, Roberto; Palma, Carlos; Aguayo, Claudio; Peña, Eduardo; Gallardo, Victoria; Guzmán-Gutiérrez, Enrique; Sáez, Tamara; Salsoso, Rocío; Sanhueza, Carlos; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

    2015-01-01

    Vascular tone is controlled by the L-arginine/nitric oxide (NO) pathway, and NO bioavailability is strongly affected by hyperglycaemia-induced oxidative stress. Insulin leads to high expression and activity of human cationic amino acid transporter 1 (hCAT-1), NO synthesis and vasodilation; thus, a protective role of insulin on high D-glucose–alterations in endothelial function is likely. Vascular reactivity to U46619 (thromboxane A2 mimetic) and calcitonin gene related peptide (CGRP) was measured in KCl preconstricted human umbilical vein rings (wire myography) incubated in normal (5 mmol/L) or high (25 mmol/L) D-glucose. hCAT-1, endothelial NO synthase (eNOS), 42 and 44 kDa mitogen-activated protein kinases (p42/44mapk), protein kinase B/Akt (Akt) expression and activity were determined by western blotting and qRT-PCR, tetrahydrobiopterin (BH4) level was determined by HPLC, and L-arginine transport (0–1000 μmol/L) was measured in response to 5–25 mmol/L D-glucose (0–36 hours) in passage 2 human umbilical vein endothelial cells (HUVECs). Assays were in the absence or presence of insulin and/or apocynin (nicotinamide adenine dinucleotide phosphate-oxidase [NADPH oxidase] inhibitor), tempol or Mn(III)TMPyP (SOD mimetics). High D-glucose increased hCAT-1 expression and activity, which was biphasic (peaks: 6 and 24 hours of incubation). High D-glucose–increased maximal transport velocity was blocked by insulin and correlated with lower hCAT-1 expression and SLC7A1 gene promoter activity. High D-glucose–increased transport parallels higher reactive oxygen species (ROS) and superoxide anion (O2•–) generation, and increased U46619-contraction and reduced CGRP-dilation of vein rings. Insulin and apocynin attenuate ROS and O2•– generation, and restored vascular reactivity to U46619 and CGRP. Insulin, but not apocynin or tempol reversed high D-glucose–increased NO synthesis; however, tempol and Mn(III)TMPyP reversed the high D-glucose–reduced BH4

  4. Insulin reverses D-glucose-increased nitric oxide and reactive oxygen species generation in human umbilical vein endothelial cells.

    PubMed

    González, Marcelo; Rojas, Susana; Avila, Pía; Cabrera, Lissette; Villalobos, Roberto; Palma, Carlos; Aguayo, Claudio; Peña, Eduardo; Gallardo, Victoria; Guzmán-Gutiérrez, Enrique; Sáez, Tamara; Salsoso, Rocío; Sanhueza, Carlos; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

    2015-01-01

    Vascular tone is controlled by the L-arginine/nitric oxide (NO) pathway, and NO bioavailability is strongly affected by hyperglycaemia-induced oxidative stress. Insulin leads to high expression and activity of human cationic amino acid transporter 1 (hCAT-1), NO synthesis and vasodilation; thus, a protective role of insulin on high D-glucose-alterations in endothelial function is likely. Vascular reactivity to U46619 (thromboxane A2 mimetic) and calcitonin gene related peptide (CGRP) was measured in KCl preconstricted human umbilical vein rings (wire myography) incubated in normal (5 mmol/L) or high (25 mmol/L) D-glucose. hCAT-1, endothelial NO synthase (eNOS), 42 and 44 kDa mitogen-activated protein kinases (p42/44mapk), protein kinase B/Akt (Akt) expression and activity were determined by western blotting and qRT-PCR, tetrahydrobiopterin (BH4) level was determined by HPLC, and L-arginine transport (0-1000 μmol/L) was measured in response to 5-25 mmol/L D-glucose (0-36 hours) in passage 2 human umbilical vein endothelial cells (HUVECs). Assays were in the absence or presence of insulin and/or apocynin (nicotinamide adenine dinucleotide phosphate-oxidase [NADPH oxidase] inhibitor), tempol or Mn(III)TMPyP (SOD mimetics). High D-glucose increased hCAT-1 expression and activity, which was biphasic (peaks: 6 and 24 hours of incubation). High D-glucose-increased maximal transport velocity was blocked by insulin and correlated with lower hCAT-1 expression and SLC7A1 gene promoter activity. High D-glucose-increased transport parallels higher reactive oxygen species (ROS) and superoxide anion (O2•-) generation, and increased U46619-contraction and reduced CGRP-dilation of vein rings. Insulin and apocynin attenuate ROS and O2•- generation, and restored vascular reactivity to U46619 and CGRP. Insulin, but not apocynin or tempol reversed high D-glucose-increased NO synthesis; however, tempol and Mn(III)TMPyP reversed the high D-glucose-reduced BH4 level. Insulin and

  5. Self-assembly of fibronectin mimetic peptide-amphiphile nanofibers.

    PubMed

    Rexeisen, Emilie L; Fan, Wei; Pangburn, Todd O; Taribagil, Rajiv R; Bates, Frank S; Lodge, Timothy P; Tsapatsis, Michael; Kokkoli, Efrosini

    2010-02-02

    Single-tailed peptide-amphiphiles have been shown to form nanofibers in solution and gel after screening of their electrostatic charges, and those containing cell-binding motifs are promising as tissue engineering scaffolds. A fibronectin-mimetic peptide sequence was developed, containing both the primary binding domain RGD and the synergy binding domain PHSRN, which has shown superior cell adhesion properties over simple RGD sequences and fibronectin in 2D culture. In order to test this sequence in a 3D environment in the future, we have designed a C(16) single-tailed peptide-amphiphile, PR_g (with a peptide headgroup of GGGSSPHSRN(SG)(5)RGDSP), that forms nanofibers and a gel in solution without any screening of its positive charge. In this study, we characterized the self-assembly properties of the PR_g peptide-amphiphile via critical micelle concentration (CMC) measurements, circular dichroism (CD) spectroscopy, cryo-transmission electron microscopy (cryo-TEM), small angle neutron scattering (SANS), and rheology measurements. The CMC of the PR_g amphiphile was determined to be 38 microM. CD measurements showed that even though the peptide formed an unordered secondary structure, the peptide-amphiphile's spectrum after aging resembled more the spectrum of an alpha+beta protein. Cryo-TEM images of a 100 microM peptide-amphiphile solution showed individual nanofibers with a diameter of approximately 10 nm and lengths on the order of several micrometers. Images taken at higher concentrations (1 mM) show a high degree of bundling among the nanofibers, and at even higher concentrations (3 and 4 mM) SANS measurements also indicated that the peptide-amphiphile formed rod-shaped structures in solution. The peptide-amphiphile gel was monitored by parallel-plate rheometry, and the elastic modulus (G') was greater than the viscous modulus (G''), which indicates that PR_g forms a gel. The shear modulus for a 2 day old gel was measured to be approximately 500 Pa, which is

  6. Recovering a MOND-like acceleration law in mimetic gravity

    NASA Astrophysics Data System (ADS)

    Vagnozzi, Sunny

    2017-09-01

    We reconsider the recently proposed mimetic gravity, focusing in particular on whether the theory is able to reproduce the inferred flat rotation curves of galaxies. We extend the theory by adding a non-minimal coupling between matter and mimetic field. Such coupling leads to the appearance of an extra force which renders the motion of test particles non-geodesic. By studying the weak field limit of the resulting equations of motion, we demonstrate that in the Newtonian limit the acceleration law induced by the non-minimal coupling reduces to a modified Newtonian dynamics (MOND)-like one. In this way, it is possible to reproduce the successes of MOND, namely the explanation for the flat galactic rotation curves and the Tully-Fisher relation, within the framework of mimetic gravity, without the need for particle dark matter. The scale-dependence of the recovered acceleration scale opens up the possibility of addressing the missing mass problem not only on galactic but also on cluster scales: we defer a full study of this issue, together with a complete analysis of fits to spiral galaxy rotation curves, to an upcoming companion paper.

  7. Dynamical behavior in mimetic F(R) gravity

    SciTech Connect

    Leon, Genly; Saridakis, Emmanuel N., E-mail: genly.leon@ucv.cl, E-mail: Emmanuel_Saridakis@baylor.edu

    2015-04-01

    We investigate the cosmological behavior of mimetic F(R) gravity. This scenario is the F(R) extension of usual mimetic gravity classes, which are based on re-parametrizations of the metric using new, but not propagating, degrees of freedom, that can lead to a wider family of solutions. Performing a detailed dynamical analysis for exponential, power-law, and arbitrary F(R) forms, we extracted the corresponding critical points. Interestingly enough, we found that although the new features of mimetic F(R) gravity can affect the universe evolution at early and intermediate times, at late times they will not have any effect, and the universe will resultmore » at stable states that coincide with those of usual F(R) gravity. However, this feature holds for the late-time background evolution only. On the contrary, the behavior of the perturbations is expected to be different since the new term contributes to the perturbations even if it does not contribute at the background level.« less

  8. Exosome mimetics: a novel class of drug delivery systems

    PubMed Central

    Kooijmans, Sander AA; Vader, Pieter; van Dommelen, Susan M; van Solinge, Wouter W; Schiffelers, Raymond M

    2012-01-01

    The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics. PMID:22619510

  9. Exosome mimetics: a novel class of drug delivery systems.

    PubMed

    Kooijmans, Sander A A; Vader, Pieter; van Dommelen, Susan M; van Solinge, Wouter W; Schiffelers, Raymond M

    2012-01-01

    The identification of extracellular phospholipid vesicles as conveyors of cellular information has created excitement in the field of drug delivery. Biological therapeutics, including short interfering RNA and recombinant proteins, are prone to degradation, have limited ability to cross biological membranes, and may elicit immune responses. Therefore, delivery systems for such drugs are under intensive investigation. Exploiting extracellular vesicles as carriers for biological therapeutics is a promising strategy to overcome these issues and to achieve efficient delivery to the cytosol of target cells. Exosomes are a well studied class of extracellular vesicles known to carry proteins and nucleic acids, making them especially suitable for such strategies. However, the considerable complexity and the related high chance of off-target effects of these carriers are major barriers for translation to the clinic. Given that it is well possible that not all components of exosomes are required for their proper functioning, an alternative strategy would be to mimic these vesicles synthetically. By assembly of liposomes harboring only crucial components of natural exosomes, functional exosome mimetics may be created. The low complexity and use of well characterized components strongly increase the pharmaceutical acceptability of such systems. However, exosomal components that would be required for the assembly of functional exosome mimetics remain to be identified. This review provides insights into the composition and functional properties of exosomes, and focuses on components which could be used to enhance the drug delivery properties of exosome mimetics.

  10. IAP Proteins Antagonist: An Introduction and Chemistry of Smac Mimetics under Clinical Development.

    PubMed

    Ali, Rafat; Singh, Shalini; Haq, Wahajul

    2018-03-12

    Smac mimetics (also known as IAP antagonist) are a new class of targeted drugs having a goal to suppress the IAPs, reestablishing the apoptotic pathways and inducing cancer cell death. Therefore, development of Smac mimetics was consideredan attractive strategy for the development of new anticancer drugs. Lots of review has been come in yesteryears which mainly discussed about biology of IAPs and their role in cancer development. But none of these reviews focused on the chemical synthesis of Smac mimetics. Literature study was done by using standard bibliographic search engines like scifinder, pubmed etc. The characteristic features of screened articles were described in the review. The review gives an introduction of IAP proteins and Smac mimetics. Readers will gain an overview of the development of Smac mimetics with representative examples of both monovalent and bivalent Smac mimetics as anticancer agents and an understanding of their structure activity relationships. Chemical synthesis of biologically important Smac mimetics was discussed briefly in this review. Small molecules that mimic Smac are continuously progressing towards clinical development. Smac mimetics are generally well tolerated and have demonstrated rapid suppression of their target (the IAPs), activation of apoptosis and anti-tumor activity. Continuous research has been done to generate even more insight into the function of IAP proteins to significantly enhance the therapeutical potential of Smac mimetics. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. Self-Assembly of a Modular Polypeptide Based on Blocks of Silk-Mimetic and Elastin-Mimetic Sequences

    DTIC Science & Technology

    2002-04-01

    blocks within the protein allowed the copolymer to spontaneously self - assemble upon heating above the phase transition of the elastin-mimetic block ... assembly of the polypeptide into a macroscopic membrane . Later we reported the synthesis and self - assembly of a copolymer incorporating this cross...UNCLASSIFIED Defense Technical Information Center Compilation Part Notice ADP014397 TITLE: Self - Assembly of a Modular Polypeptide Based on Blocks

  12. Mimetic desire and professional closure: toward a theory of intra/ inter-professional aggression.

    PubMed

    St-Pierre, Isabelle; Holmes, Dave

    2010-01-01

    The purpose of this article is to present a renewed way to theorize intra/inter-professional aggression in nursing. To this end, René Girard's mimetic mechanism and Max Weber's conception of professional closure will be explored. More specifically mimetic mechanism, summarized as a sequence of four distinct but interdependent phases including mimetic desire, mimetic rivalry, mimetic (sacrificial) crisis, and scapegoat, will serve to broaden the understanding ofintra-professional aggression. For its part, professional closure, a strategy designed to limit and control the number of individuals admitted to a specific profession, will provide a fresh perspective to critically examine the issue of inter-professional aggression by drawing attention to hidden practices of dominance and control.

  13. Late time cosmological dynamics with a nonminimal extension of the mimetic matter scenario

    NASA Astrophysics Data System (ADS)

    Hosseinkhan, N.; Nozari, K.

    2018-02-01

    We investigate an extension of mimetic gravity in which mimetic matter is nonminimally coupled to the Ricci scalar. We derive the background field equations and show that, as the minimal case, the nonminimal mimetic matter can behave as dark matter or dark energy. By adopting some well-known potentials, we study the dynamics of the scale factor and the equation of state parameter in detail. As the effective mimetic dark energy, this model explains the late time cosmic acceleration and its equation of state parameter crosses the phantom divide. We extend our analysis to the dynamical system approach and the phase space trajectories of the model. We obtain an attractor line which corresponds to the late time cosmic acceleration. By comparing this nonminimal mimetic matter scenario with observational data for the LCDM, we show that the confidence levels of this model overlap with those of Planck 2015 TT, TE, EE + Low P + Lensing + BAO data in the LCDM model.

  14. Antifreeze Protein Mimetic Metallohelices with Potent Ice Recrystallization Inhibition Activity.

    PubMed

    Mitchell, Daniel E; Clarkson, Guy; Fox, David J; Vipond, Rebecca A; Scott, Peter; Gibson, Matthew I

    2017-07-26

    Antifreeze proteins are produced by extremophile species to control ice formation and growth, and they have potential applications in many fields. There are few examples of synthetic materials which can reproduce their potent ice recrystallization inhibition property. We report that self-assembled enantiomerically pure, amphipathic metallohelicies inhibited ice growth at just 20 μM. Structure-property relationships and calculations support the hypothesis that amphipathicity is the key motif for activity. This opens up a new field of metallo-organic antifreeze protein mimetics and provides insight into the origins of ice-growth inhibition.

  15. Arginine mimetic structures in biologically active antagonists and inhibitors.

    PubMed

    Masic, Lucija Peterlin

    2006-01-01

    Peptidomimetics have found wide application as bioavailable, biostable, and potent mimetics of naturally occurring biologically active peptides. L-Arginine is a guanidino group-containing basic amino acid, which is positively charged at neutral pH and is involved in many important physiological and pathophysiological processes. Many enzymes display a preference for the arginine residue that is found in many natural substrates and in synthetic inhibitors of many trypsin-like serine proteases, e.g. thrombin, factor Xa, factor VIIa, trypsin, and in integrin receptor antagonists, used to treat many blood-coagulation disorders. Nitric oxide (NO), which is produced by oxidation of L-arginine in an NADPH- and O(2)-dependent process catalyzed by isoforms of nitric oxide synthase (NOS), exhibits diverse roles in both normal and pathological physiologies and has been postulated to be a contributor to the etiology of various diseases. Development of NOS inhibitors as well as analogs and mimetics of the natural substrate L-arginine, is desirable for potential therapeutic use and for a better understanding of their conformation when bound in the arginine binding site. The guanidino residue of arginine in many substrates, inhibitors, and antagonists forms strong ionic interactions with the carboxylate of an aspartic acid moiety, which provides specificity for the basic amino acid residue in the active side. However, a highly basic guanidino moiety incorporated in enzyme inhibitors or receptor antagonists is often associated with low selectivity and poor bioavailability after peroral application. Thus, significant effort is focused on the design and preparation of arginine mimetics that can confer selective inhibition for specific trypsin-like serine proteases and NOS inhibitors as well as integrin receptor antagonists and possess reduced basicity for enhanced oral bioavailability. This review will describe the survey of arginine mimetics designed to mimic the function of the

  16. Bis(maltolato)vanadium(III)-polypyridyl complexes: synthesis, characterization, DNA cleavage, and insulin mimetic activity.

    PubMed

    Islam, Md Nazrul; Kumbhar, Anupa A; Kumbhar, Avinash S; Zeller, Matthias; Butcher, Raymond J; Dusane, Menakshi Bhat; Joshi, Bimba N

    2010-09-20

    Four vanadium(III) complexes of the general formula [V(maltol)(2)(N-N)]ClO(4), where N-N is 2,2'-bipyridine (bpy) (1); 1,10-phenanthroline (phen) (2); dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz) (4), have been synthesized and characterized by IR, UV-visible, NMR spectroscopies, and electrospray ionization mass spectra (ESI-MS). The complexes exhibit the typical (1)H NMR spectra for paramagnetic V(III) species. The structures of complexes 1, 2, and 3 were characterized by single crystal X-ray diffraction. All complexes are monomeric and cationic containing V(III) species ligated to one neutral polypyridyl ligand and two monoanionic bidentate maltolate ligands with a distorted octahedral geometry. The complexes show an irreversible redox peak around +0.80 V versus Ag/AgCl corresponding to one-electron oxidation of V(III) to V(IV). The time-resolved UV-visible spectral changes for the complexes during the electrolysis in acetonitrile solution at +1.0 V are consistent with one-electron oxidation of the complexes to yield the stable V(IV) species. All complexes cleave plasmid pBR322 DNA without the addition of any external agents. In vitro insulin mimetic activity against insulin responsive RIN 5f cells indicates that complex 1 has similar activity to insulin while the others have moderate insulin mimetic activity.

  17. Modular protein switches derived from antibody mimetic proteins.

    PubMed

    Nicholes, N; Date, A; Beaujean, P; Hauk, P; Kanwar, M; Ostermeier, M

    2016-02-01

    Protein switches have potential applications as biosensors and selective protein therapeutics. Protein switches built by fusion of proteins with the prerequisite input and output functions are currently developed using an ad hoc process. A modular switch platform in which existing switches could be readily adapted to respond to any ligand would be advantageous. We investigated the feasibility of a modular protein switch platform based on fusions of the enzyme TEM-1 β-lactamase (BLA) with two different antibody mimetic proteins: designed ankyrin repeat proteins (DARPins) and monobodies. We created libraries of random insertions of the gene encoding BLA into genes encoding a DARPin or a monobody designed to bind maltose-binding protein (MBP). From these libraries, we used a genetic selection system for β-lactamase activity to identify genes that conferred MBP-dependent ampicillin resistance to Escherichia coli. Some of these selected genes encoded switch proteins whose enzymatic activity increased up to 14-fold in the presence of MBP. We next introduced mutations into the antibody mimetic domain of these switches that were known to cause binding to different ligands. To different degrees, introduction of the mutations resulted in switches with the desired specificity, illustrating the potential modularity of these platforms. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. The mimetic repertoire of the spotted bowerbird Ptilonorhynchus maculatus

    NASA Astrophysics Data System (ADS)

    Kelley, Laura A.; Healy, Susan D.

    2011-06-01

    Although vocal mimicry in songbirds is well documented, little is known about the function of such mimicry. One possibility is that the mimic produces the vocalisations of predatory or aggressive species to deter potential predators or competitors. Alternatively, these sounds may be learned in error as a result of their acoustic properties such as structural simplicity. We determined the mimetic repertoires of a population of male spotted bowerbirds Ptilonorhynchus maculatus, a species that mimics predatory and aggressive species. Although male mimetic repertoires contained an overabundance of vocalisations produced by species that were generally aggressive, there was also a marked prevalence of mimicry of sounds that are associated with alarm such as predator calls, alarm calls and mobbing calls, irrespective of whether the species being mimicked was aggressive or not. We propose that it may be the alarming context in which these sounds are first heard that may lead both to their acquisition and to their later reproduction. We suggest that enhanced learning capability during acute stress may explain vocal mimicry in many species that mimic sounds associated with alarm.

  19. Small-molecule SMAC mimetics as new cancer therapeutics.

    PubMed

    Bai, Longchuan; Smith, David C; Wang, Shaomeng

    2014-10-01

    Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Small-Molecule SMAC Mimetics as New Cancer Therapeutics

    PubMed Central

    Bai, Longchuan; Smith, David C.; Wang, Shaomeng

    2014-01-01

    Apoptosis is a tightly regulated cellular process and faulty regulation of apoptosis is a hallmark of human cancers. Targeting key apoptosis regulators with the goal to restore apoptosis in tumor cells has been pursued as a new cancer therapeutic strategy. XIAP, cIAP1, and cIAP2, members of inhibitor of apoptosis (IAP) proteins, are critical regulators of cell death and survival and are attractive targets for new cancer therapy. The SMAC/DIABLO protein is an endogenous antagonist of XIAP, cIAP1, and cIAP2. In the last decade, intense research efforts have resulted in the design and development of several small-molecule SMAC mimetics now in clinical trials for cancer treatment. In this review, we will discuss the roles of XIAP, cIAP1, and cIAP2 in regulation of cell death and survival, and the design and development of small-molecule SMAC mimetics as novel cancer treatments. PMID:24841289

  1. Towards echinomycin mimetics by grafting quinoxaline residues on glycophane scaffolds.

    PubMed

    Jarikote, Dilip V; Li, Wei; Jiang, Tao; Eriksson, Leif A; Murphy, Paul V

    2011-01-15

    Echinomycin is a natural depsipeptide, which is a bisintercalator, inserting quinoxaline units preferentially adjacent to CG base pairs of DNA. Herein the design and synthesis of echinomycin mimetics based on grafting of two quinoxaline residues onto a macrocyclic scaffold (glycophane) is addressed. Binding of the compounds to calf-thymus DNA was studied using UV-vis and steady state fluorescence spectroscopy, as well as thermal denaturation. An interesting observation was enhancement of fluorescence emission for the peptidomimetics on binding to DNA, which contrasted with observations for echinomycin. Molecular dynamics simulations were exploited to explore in more detail if bis-intercalation to DNA was possible for one of the glycophanes. Bis-intercalating echinomycin complexes with DNA were found to be stable during 20ns simulations at 298K. However, the MD simulations of a glycophane complexed with a DNA octamer displayed very different behaviour to echinomycin and its quinoxaline units were found to rapidly migrate out from the intercalation site. Release of bis-intercalation strain occurred with only one of the quinoxaline chromophores remaining intercalated throughout the simulation. The distance between the quinoxaline residues in the glycophane at the end of the MD simulation was 7.3-7.5Å, whereas in echinomycin, the distance between the residues was ∼11Å, suggesting that longer glycophane scaffolds would be required to generate bis-intercalating echinomycin mimetics. Copyright © 2010 Elsevier Ltd. All rights reserved.

  2. Road to Exercise Mimetics: Targeting Nuclear Receptors in Skeletal Muscle

    PubMed Central

    Fan, Weiwei; Atkins, Annette R; Yu, Ruth T.; Downes, Michael; Evans, Ronald M.

    2014-01-01

    Skeletal muscle comprises the largest organ in the human body and is the major site for energy expenditure. It exhibits remarkable plasticity in response to physiological stimuli such as exercise. Physical exercise remodels skeletal muscle and enhances its capability to burn calories, which has been shown to be beneficial for many clinical conditions including metabolic syndrome and cancer. Nuclear receptors (NRs) comprise a class of transcription factors found only in metazoans that regulate major biological processes such as reproduction, development, and metabolism. Recent studies have demonstrated crucial roles for NRs and their co-regulators in regulating skeletal muscle energy metabolism and exercise-induced muscle remodeling. While nothing can fully replace exercise, development of exercise mimetics that enhance or even substitute for the beneficial effects of physical exercise would be of great benefit. The unique property of NRs that allows modulation by endogenous or synthetic ligands makes them bona fide therapeutic targets. In this review, we present an overview of the current understanding of NRs and their co-regulators in skeletal muscle oxidative metabolism and summarize recent progress in the development of exercise mimetics that target NRs and their co-regulators. PMID:24280961

  3. Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

    PubMed Central

    Kandziora, Maja

    2014-01-01

    Summary An approach to β-D-2-aminotalose- and β-D-2-aminoidose-configured carbohydrate mimetics bearing a phenyl substituent is described. Unnatural divalent rigid p-terphenyl-linked C-aryl glycosides with 2.0 nm dimension are available using Suzuki cross-couplings. The key compound, a p-bromophenyl-substituted 1,2-oxazine, was prepared by a stereoselective [3 + 3]-cyclization of a D-isoascorbic acid-derived (Z)-nitrone and lithiated TMSE-allene. The Lewis acid-induced rearrangement of this heterocycle provided the corresponding bicyclic 1,2-oxazine derivative that may be regarded as internally protected amino sugar analogue. After subsequent reduction of the carbonyl group, the resulting bicyclic compound was used for Suzuki cross-couplings to form biphenyl aminopyran or p-terphenyl-linked dimers. Hydrogenolysis afforded new unnatural aminosugar mimetics. Zinc in the presence of acid or samarium diiodide were examined for the N–O bond cleavage in order to obtain the rigid p-terphenyl-linked C-glycosyl dimers. PMID:25161733

  4. Chronic Wound Dressings Based on Collagen-Mimetic Proteins.

    PubMed

    Cereceres, Stacy; Touchet, Tyler; Browning, Mary Beth; Smith, Clayton; Rivera, Jose; Höök, Magnus; Whitfield-Cargile, Canaan; Russell, Brooke; Cosgriff-Hernandez, Elizabeth

    2015-08-01

    Objective: Chronic wounds are projected to reach epidemic proportions due to the aging population and the increasing incidence of diabetes. There is a strong clinical need for an improved wound dressing that can balance wound moisture, promote cell migration and proliferation, and degrade at an appropriate rate to minimize the need for dressing changes. Approach: To this end, we have developed a bioactive, hydrogel microsphere wound dressing that incorporates a collagen-mimetic protein, Scl2 GFPGER , to promote active wound healing. A redesigned Scl2 GFPGER , engineered collagen (eCol GFPGER ), was created to reduce steric hindrance of integrin-binding motifs and increase overall stability of the triple helical backbone, thereby resulting in increased cell adhesion to substrates. Results: This study demonstrates the successful modification of the Scl2 GFPGER protein to eCol GFPGER , which displayed enhanced stability and integrin interactions. Fabrication of hydrogel microspheres provided a matrix with adaptive moisture technology, and degradation rates have potential for use in human wounds. Innovation: This collagen-mimetic wound dressing was designed to permit controlled modulation of cellular interactions and degradation rate without impact on other physical properties. Its fabrication into uniform hydrogel microspheres provides a bioactive dressing that can readily conform to irregular wounds. Conclusion: Overall, this new eCol GFPGER shows strong promise in the generation of bioactive hydrogels for wound healing as well as a variety of tissue scaffolds.

  5. Effect of tempol on redox homeostasis and stress tolerance in mimetically aged Drosophila.

    PubMed

    Aksu, Ugur; Yanar, Karolin; Terzioglu, Duygu; Erkol, Tugçe; Ece, Evrim; Aydin, Seval; Uslu, Ezel; Çakatay, Ufuk

    2014-09-01

    We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol, a membrane permeable antioxidant, affects the type and magnitude of oxidative damage and stress tolerance through mimetic aging process in Drosophila. Drosophila colonies were randomly divided into three groups: (1) no D-galactose, no tempol; (2) D-galactose without tempol; (3) D-galactose, but with tempol. Mimetic aging was induced by d-galactose administration. The tempol-administered flies received tempol at the concentration of 0.2% in addition to d-galactose. Thiobarbituric acid reacting substance (TBARS) concentrations, advanced oxidation protein products (AOPPs), Cu,Zn-superoxide dismutase (Cu,Zn-SOD), sialic acid (SA) were determined. Additionally, stress tolerances were tested. Mimetically aged group without tempol led to a significant decrease in tolerance to heat, cold, and starvation (P < 0.05), but tempol was used for these parameters. The Cu,Zn-SOD activity and SA concentrations were lower in both mimetically aged and tempol-administered Drosophila groups compared to control (P < 0.05), whereas there were no significantly difference between mimetically aged and tempol-administered groups. Mimetically aged group without tempol led to a significant increase in tissue TBARS and AOPPs concentrations (P < 0.05). Coadministration of tempol could prevent these alterations. Scavenging ROS using tempol also restores redox homeostasis in mimetically aged group. Tempol partly restores age-related oxidative injury and increases stress tolerance. © 2014 Wiley Periodicals, Inc.

  6. Does male preference play a role in maintaining female limited polymorphism in a Batesian mimetic butterfly?

    PubMed

    Westerman, E L; Letchinger, R; Tenger-Trolander, A; Massardo, D; Palmer, D; Kronforst, M R

    2018-05-01

    Female-limited polymorphism occurs in multiple butterfly species with Batesian mimicry. While frequency-dependent selection is often argued as the driving force behind polymorphism in Batesian mimicry systems, male preference and alternative female mating strategies may also influence the maintenance of multiple female forms. Through a series of behavioural assays with the female-limited Batesian mimetic butterfly Papilio polytes, we show that males prefer stationary mimetic females over stationary non-mimetic females, but weigh female activity levels more heavily than female wing pattern when choosing between active mimetic and active non-mimetic females. Male preference for mimetic vs. non-mimetic females is independent of male genotype at the locus responsible for the female wing pattern, the autosomal gene doublesex. However male genotype does influence their response to active females. Male emphasis on female behaviour instead of appearance may reduce sexual selection pressures on female morphology, thereby facilitating frequency-dependent natural selection due to predation risk and toxic model abundance. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Extracellular matrix-mimetic adhesive biomaterials for bone repair.

    PubMed

    Shekaran, Asha; García, Andrés J

    2011-01-01

    Limited osseointegration of current orthopedic biomaterials contributes to the failure of implants such as arthroplasties, bone screws, and bone grafts, which present a large socioeconomic cost within the United States. These implant failures underscore the need for biomimetic approaches that modulate host cell-implant material responses to enhance implant osseointegration and bone formation. Bioinspired strategies have included functionalizing implants with extracellular matrix (ECM) proteins or ECM-derived peptides or protein fragments, which engage integrins and direct osteoblast adhesion and differentiation. This review discusses (1) bone ECM composition and key integrins implicated in osteogenic differentiation, (2) the use of implants functionalized with ECM-mimetic peptides/protein fragments, and (3) growth factor-derived peptides to promote the mechanical fixation of implants to bone and to enhance bone healing within large defects. Copyright © 2010 Wiley Periodicals, Inc.

  8. Improved Oxidase Mimetic Activity by Praseodymium Incorporation into Ceria Nanocubes.

    PubMed

    Jiang, Lei; Fernandez-Garcia, Susana; Tinoco, Miguel; Yan, Zhaoxia; Xue, Qi; Blanco, Ginesa; Calvino, Jose J; Hungria, Ana B; Chen, Xiaowei

    2017-06-07

    Ceria nanocubes (NC) modified with increasing concentrations of praseodymium (5, 10, 15, and 20 mol %) have been successfully synthesized by a hydrothermal method. The as-synthesized Pr-modified ceria nanocubes exhibit an enhanced oxidase-like activity on the organic dye TMB within a wide range of concentrations and durations. The oxidase activity increases with increasing Pr amounts in Pr-modified ceria nanocubes within the investigated concentration range. Meanwhile, these Pr-modified ceria nanocubes also show higher reducibility than pure ceria nanocubes. The kinetics of their oxidase mimetic activity is fitted with the Michaelis-Menten equation. A mechanism has been proposed on how the Pr incorporation could affect the energy level of the bands in ceria and hence facilitate the TMB oxidation reaction. The presence of Pr 3+ species on the surface also contributes to the increasing activity of the Pr-modified ceria nanocubes present higher oxidase activity than pure ceria nanocubes.

  9. New diketone based vanadium complexes as insulin mimetics.

    PubMed

    Sheela, A; Roopan, S Mohana; Vijayaraghavan, R

    2008-10-01

    Since 1985, when Heyliger et al. first reported the in vivo insulin mimetic activity of oral vanadate, extensive studies exploring vanadium chemistry, including the synthesis of novel complexes and their biological effects both in vitro and in vivo have been pursued. Such complexes have emerged as possible potential agents for diabetes therapy. Among the several existing compounds, diketone based vanadium complexes have been chosen for the current study. Two new complexes namely bisdimethylmalonatooxovanadium(IV) and bisdiethylmalonatooxovanadium(IV) have been synthesized and characterized by UV-visible, FTIR and mass spectral studies. The antidiabetic activity of the complexes was proved by animal study. The results show that the above complexes have comparable antidiabetic potential with respect to the standard drug as well as with bisacetylacetonatooxovanadium(IV) which has been studied earlier by Reul et al.

  10. Towards protein-based viral mimetics for cancer therapies.

    PubMed

    Unzueta, Ugutz; Céspedes, María Virtudes; Vázquez, Esther; Ferrer-Miralles, Neus; Mangues, Ramón; Villaverde, Antonio

    2015-05-01

    High resistance and recurrence rates, together with elevated drug clearance, compel the use of maximum-tolerated drug doses in cancer therapy, resulting in high-grade toxicities and limited clinical applicability. Promoting active drug accumulation in tumor tissues would minimize such issues and improve therapeutic outcomes. A new class of therapeutic drugs suitable for the task has emerged based on the concept of virus-mimetic nanocarriers, or 'artificial viruses'. Among the spectrum of materials under exploration in nanocarrier research, proteins offer unparalleled structural and functional versatility for designing virus-like molecular vehicles. By exhibiting 'smart' functions and biomimetic traits, protein-based nanocarriers will be a step ahead of the conventional drug-protein conjugates already in the clinic in ensuring efficient delivery of passenger antitumor drugs. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Self-assembly of fibronectin mimetic peptide-amphiphile nanofibers

    NASA Astrophysics Data System (ADS)

    Rexeisen, Emilie Lynn

    Many therapeutic strategies incorporate peptides into their designs to mimic the natural protein ligands found in vivo. A few examples are the short peptide sequences RGD and PHSRN that mimic the primary and synergy-binding domains of the extracellular matrix protein, fibronectin, which is recognized by the cell surface receptor, alpha5beta 1 integrin. Even though scaffold modification with biomimetic peptides remains one of the most promising approaches for tissue engineering, the use of these peptides in therapeutic tissue-engineered products and drug delivery systems available on the commercial market is limited because the peptides are not easily able to mimic the natural protein. The design of a peptide that can effectively target the alpha5beta1 integrin would greatly increase biomimetic scaffold therapeutic potential. A novel peptide containing both the RGD primary binding domain and PHSRN synergy-binding domain for fibronectin joined with the appropriate linker should bind alpha 5beta1 integrin more efficiently and lead to greater cell adhesion over RGD alone. Several fibronectin mimetic peptides were designed and coupled to dialkyl hydrocarbon tails to make peptide-amphiphiles. The peptides contained different linkers connecting the two binding domains and different spacers separating the hydrophobic tails from the hydrophilic headgroups. The peptide-amphiphiles were deposited on mica substrates using the Langmuir-Blodgett technique. Langmuir isotherms indicated that the peptide-amphiphiles that contained higher numbers of serine residues formed a more tightly packed monolayer, but the increased number of serines also made transferring the amphiphiles to the mica substrate more difficult. Atomic force microscopy (AFM) images of the bilayers showed that the headgroups might be bent, forming small divots in the surface. These divots may help expose the PHSRN synergy-binding domain. Parallel studies undertaken by fellow group members showed that human

  12. Type I Collagen and Collagen Mimetics as Angiogenesis Promoting Superpolymers

    SciTech Connect

    Twardowski, T.; Fertala, A.; Orgel, J.P.R.O.

    2008-07-18

    Angiogenesis, the development of blood vessels from the pre-existing vasculature, is a key component of embryogenesis and tissue regeneration. Angiogenesis also drives pathologies such as tumor growth and metastasis, and hemangioma development in newborns. On the other hand, promotion of angiogenesis is needed in tissues with vascular insufficiencies, and in bioengineering, to endow tissue substitutes with appropriate microvasculatures. Therefore, much research has focused on defining mechanisms of angiogenesis, and identifying pro- and anti-angiogenic molecules. Type I collagen, the most abundant protein in humans, potently stimulates angiogenesis in vitro and in vivo. Crucial to its angiogenic activity appears to be ligationmore » and possibly clustering of endothelial cell (EC) surface {alpha}1{beta}1/{alpha}2{beta}1 integrin receptors by the GFPGER502-507 sequence of the collagen fibril. However, additional aspects of collagen structure and function that may modulate its angiogenic properties are discussed. Moreover, type I collagen and fibrin, another angiogenic polymer, share several structural features. These observations suggest strategies for creating 'angiogenic superpolymers', including: modifying type I collagen to influence its biological half-life, immunogenicity, and integrin binding capacity; genetically engineering fibrillar collagens to include additional integrin binding sites or angiogenic determinants, and remove unnecessary or deleterious sequences without compromising fibril integrity; and exploring the suitability of poly(ortho ester), PEG-lysine copolymer, tubulin, and cholesteric cuticle as collagen mimetics, and suggesting means of modifying them to display ideal angiogenic properties. The collagenous and collagen mimetic angiogenic superpolymers described here may someday prove useful for many applications in tissue engineering and human medicine.« less

  13. A mucosa-mimetic material for the mucoadhesion testing of thermogelling semi-solids.

    PubMed

    da Silva, Jéssica Bassi; Khutoryanskiy, Vitaliy V; Bruschi, Marcos L; Cook, Michael T

    2017-08-07

    Mucosa-mimetic materials are synthetic substrates which aim to replace animal tissue in mucoadhesion experiments. One potential mucosa-mimetic material is a hydrogel comprised of N-acryloyl-d-glucosamine and 2-hydroxyethylmethacrylate, which has been investigated as a surrogate for animal mucosae in the mucoadhesion testing of tablets and solution formulations. This study aims to investigate the efficacy of this mucosa-mimetic material in the testing of thermogelling semi-solid formulations, which transition from solution to gel upon warming. Two methods for assessing mucoadhesion have been used; tensile testing and a flow-through system, which allow for investigation under dramatically different conditions. It was found that the mucosa-mimetic material was a good surrogate for buccal mucosa using both testing methods. This material may be used to replace animal tissue in these experiments, potentially reducing the number of laboratory animals used in studies of this type. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. A non-linear constrained optimization technique for the mimetic finite difference method

    SciTech Connect

    Manzini, Gianmarco; Svyatskiy, Daniil; Bertolazzi, Enrico

    2014-09-30

    This is a strategy for the construction of monotone schemes in the framework of the mimetic finite difference method for the approximation of diffusion problems on unstructured polygonal and polyhedral meshes.

  15. Signal transduction mechanism of a peptide mimetic of interferon-gamma.

    PubMed

    Subramaniam, Prem S; Flowers, Lawrence O; Haider, S Mohammed I; Johnson, Howard M

    2004-05-11

    The C-terminus of interferon-gamma (IFNgamma) contains a nuclear localization sequence (NLS) required for the activation and nuclear translocation of the transcription factor STAT1alpha and induction of IFNgamma-activated genes. On the basis of this and other studies, we developed a peptide mimetic of IFNgamma that possesses the IFNgamma functions of antiviral activity and upregulation of MHC class II molecules. The mimetic also shares with IFNgamma the ability to induce the activation and nuclear translocation of STAT1alpha and the IFNgamma receptor (IFNGR)-1 subunit. The mimetic, IFNgamma(95-132), is a peptide that consists of the C-terminal residues 95-132 of murine IFNgamma and contains a required alpha-helical domain and the NLS of IFNgamma. In this study, we determined the mechanism of the intracellular action of the mimetic at the level of signal transduction. We show that the mimetic mediates the nuclear transport of IFNGR-1 through its interaction with IFNGR-1 cytoplasmic region 253-287 via both the helical region and the NLS of IFNgamma(95-132). Alanine substitutions of the NLS of the mimetic showed that the NLS was required for nuclear translocation and that the nuclear transport properties of the mimetic correlated with its ability to bind IFNGR-1. These data also show that the NLS of IFNgamma(95-132) can interact simultaneously with IFNGR-1 and the nuclear import machinery. We found that in in vitro nuclear transport assays tyrosine-phosphorylated STAT1alpha failed to undergo nuclear translocation in the presence of nuclear import factors, but was transported to nucleus in the presence of IFNgamma(95-132) and JAK2-phosphorylated IFNGR-1, to which STAT1alpha binds, as a complex of IFNgamma(95-132)/IFNGR-1/STAT1alpha. Thus, the mimetic, which possesses IFNgamma function, is directly involved as a chaperone in the nuclear transport of STAT1alpha and shares this mechanism of action with that previously described for IFNgamma. The mimetic, like IFNgamma, is

  16. A Novel Peptide Thrombopoietin Mimetic Designing and Optimization Using Computational Approach.

    PubMed

    Singh, Vimal Kishor; Kumar, Neeraj; Kalsan, Manisha; Saini, Abhishek; Chandra, Ramesh

    2016-01-01

    Thrombopoietin receptor (TPOR) is a cytokine receptor protein present on the cell surface. The activation of TPOR by thrombopoietin (TPO) (a glycoprotein hormone) triggers an intracellular cascade of megakaryocytopoiesis for the formation of platelets. Recent studies on ex vivo megakaryocytopoiesis have evolved the possibilities of therapeutics uses. These findings have paved the way for the development of various TPO alternatives (recombinant TPO, peptide, and non-peptide TPO mimetics), which are useful in regenerative medicine. However, these alternatives possess various limitations such as induction of autoimmune effects, high production cost, low specificity, and hence activity. In the present study, a novel peptidic TPO mimetic was designed through computational studies by studying the binding sites of TPO and TMP to TPOR and analogs of known mimetics. Screening of combinatorial library was done through molecular docking using ClusPro. These studies indicated mimetic-9 as a significant molecule since it was found to have better binding score of -938.8 kcal/mol with seven hydrogen bonds and a high number of hydrophobic interactions, than known mimetic TMP with docking score of -798.4 kcal/mol and TMP dimer with docking score of -811.9 kcal/mol for TPOR. Mimetic9-TPOR complex was further assessed by the molecular dynamics simulation, and their complex was found to be stable with an RMSD value of 0.091 Å. While studying the parameters, mimetic-9 was found to have overall good physiochemical properties with positive grand average hydropathy (GRAVY) score and high instability index score and was found to be localized in the extracellular region. The designed mimetic-9 might prove to be a useful lead molecule for mimicking the role of TPO for in vitro platelet production with higher efficiency.

  17. Plant-mimetic Heat Pipes for Operation with Large Inertial and Gravitational Stresses

    DTIC Science & Technology

    2015-08-07

    SUBTITLE Plant -mimetic heat pipes for operation with large inertial and gravitational stresses 5a.  CONTRACT NUMBER 5b.  GRANT NUMBER FA9550-12-1-0227 5c... plants to propose plant -inspired designs of loop heat pipes for operation with large stresses . Toward the realization of these Superheated Loop Heat ...Title: PLANT -MIMETIC HEAT PIPES FOR OPERATION WITH LARGE INERTIAL AND GRAVITATIONAL STRESSES P.I.: Abraham Stroock, Chemical and Biomolecular

  18. Smac mimetics and oncolytic viruses synergize in driving anticancer T-cell responses through complementary mechanisms.

    PubMed

    Kim, Dae-Sun; Dastidar, Himika; Zhang, Chunfen; Zemp, Franz J; Lau, Keith; Ernst, Matthias; Rakic, Andrea; Sikdar, Saif; Rajwani, Jahanara; Naumenko, Victor; Balce, Dale R; Ewanchuk, Ben W; Taylor, Pankaj; Yates, Robin M; Jenne, Craig; Gafuik, Chris; Mahoney, Douglas J

    2017-08-24

    Second mitochondrial activator of caspase (Smac)-mimetic compounds and oncolytic viruses were developed to kill cancer cells directly. However, Smac-mimetic compound and oncolytic virus therapies also modulate host immune responses in ways we hypothesized would complement one another in promoting anticancer T-cell immunity. We show that Smac-mimetic compound and oncolytic virus therapies synergize in driving CD8 + T-cell responses toward tumors through distinct activities. Smac-mimetic compound treatment with LCL161 reinvigorates exhausted CD8 + T cells within immunosuppressed tumors by targeting tumor-associated macrophages for M1-like polarization. Oncolytic virus treatment with vesicular stomatitis virus (VSV ΔM51 ) promotes CD8 + T-cell accumulation within tumors and CD8 + T-cell activation within the tumor-draining lymph node. When combined, LCL161 and VSV ΔM51 therapy engenders CD8 + T-cell-mediated tumor control in several aggressive mouse models of cancer. Smac-mimetic compound and oncolytic virus therapies are both in clinical development and their combination therapy represents a promising approach for promoting anticancer T-cell immunity.Oncolytic viruses (OV) and second mitochondrial activator of caspase (Smac)-mimetic compounds (SMC) synergistically kill cancer cells directly. Here, the authors show that SMC and OV therapies combination also synergize in vivo by promoting anticancer immunity through an increase in CD8 + T-cell response.

  19. Mimetic Divergence and the Speciation Continuum in the Mimic Poison Frog Ranitomeya imitator.

    PubMed

    Twomey, Evan; Vestergaard, Jacob S; Venegas, Pablo J; Summers, Kyle

    2016-02-01

    While divergent ecological adaptation can drive speciation, understanding the factors that facilitate or constrain this process remains a major goal in speciation research. Here, we study two mimetic transition zones in the poison frog Ranitomeya imitator, a species that has undergone a Müllerian mimetic radiation to establish four morphs in Peru. We find that mimetic morphs are strongly phenotypically differentiated, producing geographic clines with varying widths. However, distinct morphs show little neutral genetic divergence, and landscape genetic analyses implicate isolation by distance as the primary determinant of among-population genetic differentiation. Mate choice experiments suggest random mating at the transition zones, although certain allopatric populations show a preference for their own morph. We present evidence that this preference may be mediated by color pattern specifically. These results contrast with an earlier study of a third transition zone, in which a mimetic shift was associated with reproductive isolation. Overall, our results suggest that the three known mimetic transition zones in R. imitator reflect a speciation continuum, which we have characterized at the geographic, phenotypic, behavioral, and genetic levels. We discuss possible explanations for variable progress toward speciation, suggesting that multifarious selection on both mimetic color pattern and body size may be responsible for generating reproductive isolation.

  20. How sound symbolism is processed in the brain: a study on Japanese mimetic words.

    PubMed

    Kanero, Junko; Imai, Mutsumi; Okuda, Jiro; Okada, Hiroyuki; Matsuda, Tetsuya

    2014-01-01

    Sound symbolism is the systematic and non-arbitrary link between word and meaning. Although a number of behavioral studies demonstrate that both children and adults are universally sensitive to sound symbolism in mimetic words, the neural mechanisms underlying this phenomenon have not yet been extensively investigated. The present study used functional magnetic resonance imaging to investigate how Japanese mimetic words are processed in the brain. In Experiment 1, we compared processing for motion mimetic words with that for non-sound symbolic motion verbs and adverbs. Mimetic words uniquely activated the right posterior superior temporal sulcus (STS). In Experiment 2, we further examined the generalizability of the findings from Experiment 1 by testing another domain: shape mimetics. Our results show that the right posterior STS was active when subjects processed both motion and shape mimetic words, thus suggesting that this area may be the primary structure for processing sound symbolism. Increased activity in the right posterior STS may also reflect how sound symbolic words function as both linguistic and non-linguistic iconic symbols.

  1. How Sound Symbolism Is Processed in the Brain: A Study on Japanese Mimetic Words

    PubMed Central

    Okuda, Jiro; Okada, Hiroyuki; Matsuda, Tetsuya

    2014-01-01

    Sound symbolism is the systematic and non-arbitrary link between word and meaning. Although a number of behavioral studies demonstrate that both children and adults are universally sensitive to sound symbolism in mimetic words, the neural mechanisms underlying this phenomenon have not yet been extensively investigated. The present study used functional magnetic resonance imaging to investigate how Japanese mimetic words are processed in the brain. In Experiment 1, we compared processing for motion mimetic words with that for non-sound symbolic motion verbs and adverbs. Mimetic words uniquely activated the right posterior superior temporal sulcus (STS). In Experiment 2, we further examined the generalizability of the findings from Experiment 1 by testing another domain: shape mimetics. Our results show that the right posterior STS was active when subjects processed both motion and shape mimetic words, thus suggesting that this area may be the primary structure for processing sound symbolism. Increased activity in the right posterior STS may also reflect how sound symbolic words function as both linguistic and non-linguistic iconic symbols. PMID:24840874

  2. Bicontinuous microemulsions as a biomembrane mimetic system for melittin

    DOE PAGES

    Hayes, Douglas G.; Ye, Ran; Dunlap, Rachel N.; ...

    2017-11-12

    Antimicrobial peptides effectively kill antibiotic-resistant bacteria by forming pores in prokaryotes' biomembranes via penetration into the biomembranes' interior. Bicontinuous microemulsions, consisting of interdispersed oil and water nanodomains separated by flexible surfactant monolayers, are potentially valuable for hosting membrane-associated peptides and proteins due to their thermodynamic stability, optical transparency, low viscosity, and high interfacial area. Here, we show that bicontinuous microemulsions formed by negatively-charged surfactants are a robust biomembrane mimetic system for the antimicrobial peptide melittin. When encapsulated in bicontinuous microemulsions formed using three-phase (Winsor-III) systems, melittin's helicity increases greatly due to penetration into the surfactant monolayers, mimicking its behavior inmore » biomembranes. But, the threshold melittin concentration required to achieve these trends is lower for the microemulsions. The extent of penetration was decreased when the interfacial fluidity of the microemulsions was increased. In conclusion, these results suggest the utility of bicontinuous microemulsions for isolation, purification, delivery, and host systems for antimicrobial peptides.« less

  3. Promotion of hair growth by newly synthesized ceramide mimetic compound.

    PubMed

    Park, Bu-Mahn; Bak, Soon-Sun; Shin, Kyung-Oh; Kim, Minhee; Kim, Daehwan; Jung, Sang-Hun; Jeong, Sekyoo; Sung, Young Kwan; Kim, Hyun Jung

    2017-09-09

    Based on the crucial roles of ceramides in skin barrier function, use of ceramides or their structural mimetic compounds, pseudoceramides, as cosmetic ingredients are getting more popular. While currently used pseudoceramides are intended to substitute the structural roles of ceramides in stratum corneum, development of bioactive pseudoceramides has been repeatedly reported. In this study, based on the potential involvement of sphingolipids in hair cycle regulation, we investigated the effects of newly synthesized pseudoceramide, bis-oleamido isopropyl alcohol (BOI), on hair growth using cultured human hair follicles and animal models. BOI treatment promoted hair growth in cultured human hair follicles ex vivo and induced earlier conversion of telogen into anagen. Although we did not find a significant enhancement of growth factor expression and follicular cell proliferation, BOI treatment resulted in an increased sphinganine and sphingosine contents as well as increased ceramides contents in cultured dermal papilla (DP) cells. Taken together, our data strongly suggest that biologically active pseudoceramide promotes hair growth by stimulating do novo synthesis of sphingolipids in DP cells. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Membrane mimetic surface functionalization of nanoparticles: Methods and applications

    PubMed Central

    Weingart, Jacob; Vabbilisetty, Pratima; Sun, Xue-Long

    2013-01-01

    Nanoparticles (NPs), due to their size-dependent physical and chemical properties, have shown remarkable potential for a wide range of applications over the past decades. Particularly, the biological compatibilities and functions of NPs have been extensively studied for expanding their potential in areas of biomedical application such as bioimaging, biosensing, and drug delivery. In doing so, surface functionalization of NPs by introducing synthetic ligands and/or natural biomolecules has become a critical component in regards to the overall performance of the NP system for its intended use. Among known examples of surface functionalization, the construction of an artificial cell membrane structure, based on phospholipids, has proven effective in enhancing biocompatibility and has become a viable alternative to more traditional modifications, such as direct polymer conjugation. Furthermore, certain bioactive molecules can be immobilized onto the surface of phospholipid platforms to generate displays more reminiscent of cellular surface components. Thus, NPs with membrane-mimetic displays have found use in a range of bioimaging, biosensing, and drug delivery applications. This review herein describes recent advances in the preparations and characterization of integrated functional NPs covered by artificial cell membrane structures and their use in various biomedical applications. PMID:23688632

  5. Metal stabilization of collagen and de novo designed mimetic peptides

    PubMed Central

    Parmar, Avanish S.; Xu, Fei; Pike, Douglas H.; Belure, Sandeep V.; Hasan, Nida F.; Drzewiecki, Kathryn E.; Shreiber, David I.; Nanda, Vikas

    2017-01-01

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix. PMID:26225466

  6. Determination of superoxide dismutase mimetic activity in common culinary herbs.

    PubMed

    Chohan, Magali; Naughton, Declan P; Opara, Elizabeth I

    2014-01-01

    Under conditions of oxidative stress, the removal of superoxide, a free radical associated with chronic inflammation, is catalysed by superoxide dismutase (SOD). Thus in addition to acting as an antioxidant, SOD may also be utilized as an anti-inflammatory agent. Some plant derived foods have been shown to have SOD mimetic (SODm) activity however it is not known if this activity is possessed by culinary herbs which have previously been shown to possess both antioxidant and anti-inflammatory properties. The aim of the study was to ascertain if the culinary herbs rosemary, sage and thyme possess SODm activity, and to investigate the influence of cooking and digestion on this activity. Transition metal ion content was also determined to establish if it could likely contribute to any SODm activity detected. All extracts of uncooked (U), cooked (C) and cooked and digested (C&D) herbs were shown to possess SODm activity, which was significantly correlated with previously determined antioxidant and anti-inflammatory activities of these herbs. SODm activity was significantly increased following (C) and (C&D) for rosemary and sage only. The impact of (C) and (C&D) on the SODm for thyme may have been influenced by its transition metal ion content. SODm activity may contribute to the herbs' antioxidant and anti-inflammatory activities however the source and significance of this activity need to be established.

  7. A manganese porphyrin superoxide dismutase mimetic enhances tumor radioresponsiveness

    SciTech Connect

    Moeller, Benjamin J.; Batinic-Haberle, Ines; Spasojevic, Ivan

    2005-10-01

    Purpose: To determine the effect of the superoxide dismutase mimetic Mn(III) tetrakis(N-ethylpyridinium-2-yl)porphyrin (MnTE-2-PyP{sup 5+}) on tumor radioresponsiveness. Methods and Materials: Various rodent tumor (4T1, R3230, B16) and endothelial (SVEC) cell lines were exposed to MnTE-2-PyP{sup 5+} and assayed for viability and radiosensitivity in vitro. Next, tumors were treated with radiation and MnTE-2-PyP{sup 5+} in vivo, and the effects on tumor growth and vascularity were monitored. Results: In vitro, MnTE-2-PyP{sup 5+} was not significantly cytotoxic. However, at concentrations as low as 2 {mu}mol/L it caused 100% inhibition of secretion by tumor cells of cytokines protective of irradiated endothelial cells. In vivo,more » combined treatment with radiation and MnTE-2-PyP{sup 5+} achieved synergistic tumor devascularization, reducing vascular density by 78.7% within 72 h of radiotherapy (p < 0.05 vs. radiation or drug alone). Co-treatment of tumors also resulted in synergistic antitumor effects, extending tumor growth delay by 9 days (p < 0.01). Conclusions: These studies support the conclusion that MnTE-2-PyP{sup 5+}, which has been shown to protect normal tissues from radiation injury, can also improve tumor control through augmenting radiation-induced damage to the tumor vasculature.« less

  8. The therapeutic potential of insulin-mimetic vanadium complexes.

    PubMed

    Sakurai, Hiromu; Yasui, Hiroyuki; Adachi, Yusuke

    2003-07-01

    Throughout the world, the number of patients suffering from diabetes mellitus (DM) is increasing on a daily basis, probably due to change in lifestyle. DM is mainly classified as either insulin-dependent Type 1 or non-insulin-dependent Type 2, according to the definition of WHO. To treat DM, which has many severe complications, several types of insulin preparations and synthetic drugs for Type 1 and Type 2 DM, respectively, have been developed and are in clinical use. However, there are several problems concerning the insulin preparations and synthetic drugs, such as physical and mental pain due to daily insulin injections and defects involving side effects, respectively. Consequently, a new class of therapeutic agents is anticipated. For this purpose, vanadium-containing complexes are expected to treat or improve both types of DM by using unique characteristics of the transition metal. In this article, the current state of research on insulin-mimetic vanadium complexes are reviewed, with special focus on the paramagnetic vanadyl (+4 oxidation state of vanadium) complexes with different coordination modes. To analyse the blood glucose-lowering effects of the vanadyl complexes, new results on the organ distribution and pharmacokinetic analysis of the vanadyl state in the blood of rats are also described.

  9. Oral insulin-mimetic compounds that act independently of insulin.

    PubMed

    García-Vicente, Silvia; Yraola, Francesc; Marti, Luc; González-Muñoz, Elena; García-Barrado, María José; Cantó, Carles; Abella, Anna; Bour, Sandy; Artuch, Rafael; Sierra, Cristina; Brandi, Nuria; Carpéné, Christian; Moratinos, Julio; Camps, Marta; Palacín, Manuel; Testar, Xavier; Gumà, Anna; Albericio, Fernando; Royo, Miriam; Mian, Alec; Zorzano, Antonio

    2007-02-01

    The hallmarks of insulin action are the stimulation and suppression of anabolic and catabolic responses, respectively. These responses are orchestrated by the insulin pathway and are initiated by the binding of insulin to the insulin receptor, which leads to activation of the receptor's intrinsic tyrosine kinase. Severe defects in the insulin pathway, such as in types A and B and advanced type 1 and 2 diabetes lead to severe insulin resistance, resulting in a partial or complete absence of response to exogenous insulin and other known classes of antidiabetes therapies. We have characterized a novel class of arylalkylamine vanadium salts that exert potent insulin-mimetic effects downstream of the insulin receptor in adipocytes. These compounds trigger insulin signaling, which is characterized by rapid activation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3 independent of insulin receptor phosphorylation. Administration of these compounds to animal models of diabetes lowered glycemia and normalized the plasma lipid profile. Arylalkylamine vanadium compounds also showed antidiabetic effects in severely diabetic rats with undetectable circulating insulin. These results demonstrate the feasibility of insulin-like regulation in the complete absence of insulin and downstream of the insulin receptor. This represents a novel therapeutic approach for diabetic patients with severe insulin resistance.

  10. Designing ECM-mimetic materials using protein engineering.

    PubMed

    Cai, Lei; Heilshorn, Sarah C

    2014-04-01

    The natural extracellular matrix (ECM), with its multitude of evolved cell-instructive and cell-responsive properties, provides inspiration and guidelines for the design of engineered biomaterials. One strategy to create ECM-mimetic materials is the modular design of protein-based engineered ECM (eECM) scaffolds. This modular design strategy involves combining multiple protein domains with different functionalities into a single, modular polymer sequence, resulting in a multifunctional matrix with independent tunability of the individual domain functions. These eECMs often enable decoupled control over multiple material properties for fundamental studies of cell-matrix interactions. In addition, since the eECMs are frequently composed entirely of bioresorbable amino acids, these matrices have immense clinical potential for a variety of regenerative medicine applications. This brief review demonstrates how fundamental knowledge gained from structure-function studies of native proteins can be exploited in the design of novel protein-engineered biomaterials. While the field of protein-engineered biomaterials has existed for over 20years, the community is only now beginning to fully explore the diversity of functional peptide modules that can be incorporated into these materials. We have chosen to highlight recent examples that either (i) demonstrate exemplary use as matrices with cell-instructive and cell-responsive properties or (ii) demonstrate outstanding creativity in terms of novel molecular-level design and macro-level functionality. Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  11. SOCS1 Mimetic Peptide Suppresses Chronic Intraocular Inflammatory Disease (Uveitis)

    PubMed Central

    He, Chang; Yu, Cheng-Rong; Mattapallil, Mary J.; Sun, Lin

    2016-01-01

    Uveitis is a potentially sight-threatening disease characterized by repeated cycles of remission and recurrent inflammation. The JAK/STAT pathway regulates the differentiation of pathogenic Th1 and Th17 cells that mediate uveitis. A SOCS1 mimetic peptide (SOCS1-KIR) that inhibits JAK2/STAT1 pathways has recently been shown to suppress experimental autoimmune uveitis (EAU). However, it is not clear whether SOCS1-KIR ameliorated uveitis by targeting JAK/STAT pathways of pathogenic lymphocytes or via inhibition of macrophages and antigen-presenting cells that also enter the retina during EAU. To further investigate mechanisms that mediate SOCS1-KIR effects and evaluate the efficacy of SOCS1-KIR as an investigational drug for chronic uveitis, we induced EAU in rats by adoptive transfer of uveitogenic T-cells and monitored disease progression and severity by slit-lamp microscopy, histology, and optical coherence tomography. Topical administration of SOCS1-KIR ameliorated acute and chronic posterior uveitis by inhibiting Th17 cells and the recruitment of inflammatory cells into retina while promoting expansion of IL-10-producing Tregs. We further show that SOCS1-KIR conferred protection of resident retinal cells that play critical role in vision from cytotoxic effects of inflammatory cytokines by downregulating proapoptotic genes. Thus, SOCS1-KIR suppresses uveitis and confers neuroprotective effects and might be exploited as a noninvasive treatment for chronic uveitis. PMID:27703302

  12. Basal Lamina Mimetic Nanofibrous Peptide Networks for Skeletal Myogenesis

    NASA Astrophysics Data System (ADS)

    Yasa, I. Ceren; Gunduz, Nuray; Kilinc, Murat; Guler, Mustafa O.; Tekinay, Ayse B.

    2015-11-01

    Extracellular matrix (ECM) is crucial for the coordination and regulation of cell adhesion, recruitment, differentiation and death. Therefore, equilibrium between cell-cell and cell-matrix interactions and matrix-associated signals are important for the normal functioning of cells, as well as for regeneration. In this work, we describe importance of adhesive signals for myoblast cells’ growth and differentiation by generating a novel ECM mimetic peptide nanofiber scaffold system. We show that not only structure but also composition of bioactive signals are important for cell adhesion, growth and differentiation by mimicking the compositional and structural properties of native skeletal muscle basal lamina. We conjugated laminin-derived integrin binding peptide sequence, “IKVAV”, and fibronectin-derived well known adhesive sequence, “RGD”, into peptide nanostructures to provide adhesive and myogenic cues on a nanofibrous morphology. The myogenic and adhesive signals exhibited a synergistic effect on model myoblasts, C2C12 cells. Our results showed that self-assembled peptide nanofibers presenting laminin derived epitopes support adhesion, growth and proliferation of the cells and significantly promote the expression of skeletal muscle-specific marker genes. The functional peptide nanofibers used in this study present a biocompatible and biodegradable microenvironment, which is capable of supporting the growth and differentiation of C2C12 myoblasts into myotubes.

  13. Metal Stabilization of Collagen and de Novo Designed Mimetic Peptides.

    PubMed

    Parmar, Avanish S; Xu, Fei; Pike, Douglas H; Belure, Sandeep V; Hasan, Nida F; Drzewiecki, Kathryn E; Shreiber, David I; Nanda, Vikas

    2015-08-18

    We explore the design of metal binding sites to modulate triple-helix stability of collagen and collagen-mimetic peptides. Globular proteins commonly utilize metals to connect tertiary structural elements that are well separated in sequence, constraining structure and enhancing stability. It is more challenging to engineer structural metals into fibrous protein scaffolds, which lack the extensive tertiary contacts seen in globular proteins. In the collagen triple helix, the structural adjacency of the carboxy-termini of the three chains makes this region an attractive target for introducing metal binding sites. We engineered His3 sites based on structural modeling constraints into a series of designed homotrimeric and heterotrimeric peptides, assessing the capacity of metal binding to improve stability and in the case of heterotrimers, affect specificity of assembly. Notable enhancements in stability for both homo- and heteromeric systems were observed upon addition of zinc(II) and several other metal ions only when all three histidine ligands were present. Metal binding affinities were consistent with the expected Irving-Williams series for imidazole. Unlike other metals tested, copper(II) also bound to peptides lacking histidine ligands. Acetylation of the peptide N-termini prevented copper binding, indicating proline backbone amide metal-coordination at this site. Copper similarly stabilized animal extracted Type I collagen in a metal-specific fashion, highlighting the potential importance of metal homeostasis within the extracellular matrix.

  14. PKC activation sensitizes basal-like breast cancer cell lines to Smac mimetics.

    PubMed

    Cornmark, L; Holmgren, C; Masoumi, K; Larsson, C

    2016-01-01

    There is a need for novel strategies to initiate cancer cell death. One approach is the use of Smac mimetics, which antagonize inhibitor of apoptosis proteins (IAPs). Recent studies have shown that combinations of Smac mimetics such as LBW242 or LCL161 in combination with chemotherapeutic agents increase cancer cell death. Here we show that the protein kinase C (PKC) activator TPA together with the Smac mimetic LBW242 induces cell death in two basal breast cancer cell lines (MDA-MB-468 and BT-549) that are resistant to Smac mimetic as single agent. Ten other LBW242-insensitive cancer cell lines were not influenced by the TPA+LBW242 combination. The TPA+LBW242 effect was suppressed by the PKC inhibitor GF109203X, indicating dependence on PKC enzymatic activity. The PKC effect was mediated via increased synthesis and release of TNFα, which can induce death in the presence of Smac mimetics. The cell death, coinciding with caspase-3 cleavage, was suppressed by caspase inhibition and preceded by the association of RIP1 with caspase-8, as seen in complex II formation. Smac mimetics, but not TPA, induced the non-canonical NF-κB pathway in both MDA-MB-231 and MDA-MB-468 cells. Blocking the canonical NF-κB pathway suppressed TPA induction of TNFα in MDA-MB-468 cells whereas isolated downregulation of either the canonical or non-canonical pathways did not abolish the Smac mimetic induction of the NF-κB driven genes TNFα and BIRC3 in MDA-MB-231 cells although the absolute levels were suppressed. A combined downregulation of the canonical and non-canonical pathways further suppressed TNFα levels and inhibited Smac mimetic-mediated cell death. Our data suggest that in certain basal breast cancer cell lines co-treatment of TPA with a Smac mimetic induces cell death highlighting the potential of using these pathways as molecular targets for basal-like breast cancers.

  15. Reactive oxygen species contribute toward Smac mimetic/temozolomide-induced cell death in glioblastoma cells.

    PubMed

    Seyfrid, Mathieu; Marschall, Viola; Fulda, Simone

    2016-11-01

    Small-molecule inhibitors of Inhibitor of Apoptosis proteins such as Smac mimetics have been reported to provide a promising tool to sensitize glioblastoma (GBM) cells to cytotoxic therapies including chemotherapeutic drugs. However, the underlying molecular mechanisms of action have not yet been fully unraveled. In the present study, we therefore investigated the role of reactive oxygen species (ROS) in the regulation of Smac mimetic/temozolomide (TMZ)-induced cell death in GBM cells. Here, we show that the Smac mimetic BV6 and TMZ act in concert to stimulate the production of both cytosolic and mitochondrial ROS. This accumulation of ROS contributes toward the activation of the proapoptotic factor BAX upon BV6/TMZ cotreatment as several ROS scavengers (i.e. N-acetyl-L-cysteine, MnTBAP, or α-tocopherol) protect GBM cells against BV6/TMZ-mediated BAX activation. In addition, ROS scavengers significantly rescue GBM cells from BV6/TMZ-triggered cell death, indicating that ROS generation is required for the induction of cell death. By showing that ROS play an important role in the regulation of Smac mimetic/TMZ-induced cell death, our work sheds light on the crucial role of the oxidative system in the cooperative antitumor activity of Smac mimetic/TMZ combination therapy against GBM cells.

  16. Elementary dispersion analysis of some mimetic discretizations on triangular C-grids

    SciTech Connect

    Korn, P., E-mail: peter.korn@mpimet.mpg.de; Danilov, S.; A.M. Obukhov Institute of Atmospheric Physics, Moscow

    2017-02-01

    Spurious modes supported by triangular C-grids limit their application for modeling large-scale atmospheric and oceanic flows. Their behavior can be modified within a mimetic approach that generalizes the scalar product underlying the triangular C-grid discretization. The mimetic approach provides a discrete continuity equation which operates on an averaged combination of normal edge velocities instead of normal edge velocities proper. An elementary analysis of the wave dispersion of the new discretization for Poincaré, Rossby and Kelvin waves shows that, although spurious Poincaré modes are preserved, their frequency tends to zero in the limit of small wavenumbers, which removes the divergence noisemore » in this limit. However, the frequencies of spurious and physical modes become close on shorter scales indicating that spurious modes can be excited unless high-frequency short-scale motions are effectively filtered in numerical codes. We argue that filtering by viscous dissipation is more efficient in the mimetic approach than in the standard C-grid discretization. Lumping of mass matrices appearing with the velocity time derivative in the mimetic discretization only slightly reduces the accuracy of the wave dispersion and can be used in practice. Thus, the mimetic approach cures some difficulties of the traditional triangular C-grid discretization but may still need appropriately tuned viscosity to filter small scales and high frequencies in solutions of full primitive equations when these are excited by nonlinear dynamics.« less

  17. Beyond Antibodies as Binding Partners: The Role of Antibody Mimetics in Bioanalysis.

    PubMed

    Yu, Xiaowen; Yang, Yu-Ping; Dikici, Emre; Deo, Sapna K; Daunert, Sylvia

    2017-06-12

    The emergence of novel binding proteins or antibody mimetics capable of binding to ligand analytes in a manner analogous to that of the antigen-antibody interaction has spurred increased interest in the biotechnology and bioanalytical communities. The goal is to produce antibody mimetics designed to outperform antibodies with regard to binding affinities, cellular and tumor penetration, large-scale production, and temperature and pH stability. The generation of antibody mimetics with tailored characteristics involves the identification of a naturally occurring protein scaffold as a template that binds to a desired ligand. This scaffold is then engineered to create a superior binder by first creating a library that is then subjected to a series of selection steps. Antibody mimetics have been successfully used in the development of binding assays for the detection of analytes in biological samples, as well as in separation methods, cancer therapy, targeted drug delivery, and in vivo imaging. This review describes recent advances in the field of antibody mimetics and their applications in bioanalytical chemistry, specifically in diagnostics and other analytical methods.

  18. Prey from the eyes of predators: Color discriminability of aposematic and mimetic butterflies from an avian visual perspective.

    PubMed

    Su, Shiyu; Lim, Matthew; Kunte, Krushnamegh

    2015-11-01

    Predation exerts strong selection on mimetic butterfly wing color patterns, which also serve other functions such as sexual selection. Therefore, specific selection pressures may affect the sexes and signal components differentially. We tested three predictions about the evolution of mimetic resemblance by comparing wing coloration of aposematic butterflies and their Batesian mimics: (a) females gain greater mimetic advantage than males and therefore are better mimics, (b) due to intersexual genetic correlations, sexually monomorphic mimics are better mimics than female-limited mimics, and (c) mimetic resemblance is better on the dorsal wing surface that is visible to predators in flight. Using a physiological model of avian color vision, we quantified mimetic resemblance from predators' perspective, which showed that female butterflies were better mimics than males. Mimetic resemblance in female-limited mimics was comparable to that in sexually monomorphic mimics, suggesting that intersexual genetic correlations did not constrain adaptive response to selection for female-limited mimicry. Mimetic resemblance on the ventral wing surface was better than that on the dorsal wing surface, implying stronger natural and sexual selection on ventral and dorsal surfaces, respectively. These results suggest that mimetic resemblance in butterfly mimicry rings has evolved under various selective pressures acting in a sex- and wing surface-specific manner. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

  19. René Girard and the Mimetic Nature of Eating Disorders.

    PubMed

    Strand, Mattias

    2018-03-07

    French historian and literary critic René Girard (1923-2015), most widely known for the concepts of mimetic desire and scapegoating, also engaged in the discussion of the surge of eating disorders in his 1996 essay Eating Disorders and Mimetic Desire. This article explores Girard's ideas on the mimetic nature and origin of eating disorders from a clinical psychiatric perspective and contextualizes them within the field of eating disorders research as well as in relation to broader psychological, sociological and anthropological models of social comparison and non-consumption. Three main themes in Girard's thinking on the topic of eating disorders are identified and explored: the 'end of prohibitions' as a driving force in the emergence of eating disorders, eating disorders as a phenomenon specific to modernity, and the significance of 'conspicuous non-consumption' in the emergence of eating disorders.

  20. The arbitrary order mixed mimetic finite difference method for the diffusion equation

    DOE PAGES

    Gyrya, Vitaliy; Lipnikov, Konstantin; Manzini, Gianmarco

    2016-05-01

    Here, we propose an arbitrary-order accurate mimetic finite difference (MFD) method for the approximation of diffusion problems in mixed form on unstructured polygonal and polyhedral meshes. As usual in the mimetic numerical technology, the method satisfies local consistency and stability conditions, which determines the accuracy and the well-posedness of the resulting approximation. The method also requires the definition of a high-order discrete divergence operator that is the discrete analog of the divergence operator and is acting on the degrees of freedom. The new family of mimetic methods is proved theoretically to be convergent and optimal error estimates for flux andmore » scalar variable are derived from the convergence analysis. A numerical experiment confirms the high-order accuracy of the method in solving diffusion problems with variable diffusion tensor. It is worth mentioning that the approximation of the scalar variable presents a superconvergence effect.« less

  1. Dual action Smac mimetics-zinc chelators as pro-apoptotic antitumoral agents.

    PubMed

    Manzoni, Leonardo; Gornati, Davide; Manzotti, Mattia; Cairati, Silvia; Bossi, Alberto; Arosio, Daniela; Lecis, Daniele; Seneci, Pierfausto

    2016-10-01

    Dual action compounds (DACs) based on 4-substituted aza-bicyclo[5.3.0]decane Smac mimetic scaffolds (ABDs) linked to a Zn(2+)-chelating moiety (DPA, o-hydroxy, m-allyl, N-acyl (E)-phenylhydrazone) through their 10 position are reported and characterized. Their synthesis, their target affinity (XIAP BIR3, Zn(2+)) in cell-free assays, their pro-apoptotic effects and cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. The results are interpreted to evaluate the influence of Zn(2+) chelators on cell-free potency and on cellular permeability of DACs, and to propose novel avenues towards more potent antitumoral DACs based on Smac mimetics and Zn(2+) chelation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. Establishment of the mimetic aging effect in mice caused by D-galactose.

    PubMed

    Ho, Shih-Ching; Liu, Jue-Hao; Wu, ReY-Yih

    2003-01-01

    We successfully established an oxidant damage of mimetic aging model using mice induced by D-galactose, and the mimetic aging model is relative to free radical and the accumulation of waste substances in metabolism. The animals were divided into 3 groups: (1) phosphate-buffered saline (PBS); (2) 1% D-galactose; (3) 5% D-galactose by subcutaneous injection every day. After 45 days, mice treated with D-galactose showed a significant increase in the malondialdehyde (MDA), total antioxidant status (TAS) and a decrease in superoxide dismutase (SOD) in the blood compared with the PBS group. In the brain, the D-galactose treated mice exhibited a higher level MDA and a lower level SOD activity. In the liver, only the 5% D-galactose group indicated a significant increase in MDA. By reference to the oxidative biomarkers in blood, brain and liver, we have confirmed the reliability of the mimetic aging model.

  3. Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

    NASA Astrophysics Data System (ADS)

    Hirano, Shin'ichi; Nishi, Sakine; Kobayashi, Tsutomu

    2017-07-01

    We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which is free from ghost and gradient instabilities. As a side remark, we also show that mimetic F(Script R) theory is plagued with the Ostrogradsky instability.

  4. A review of underwater bio-mimetic propulsion: cruise and fast-start

    NASA Astrophysics Data System (ADS)

    Chao, Li-Ming; Cao, Yong-Hui; Pan, Guang

    2017-08-01

    This paper reviews recent developments in the understanding of underwater bio-mimetic propulsion. Two impressive models of underwater propulsion are considered: cruise and fast-start. First, we introduce the progression of bio-mimetic propulsion, especially underwater propulsion, where some primary conceptions are touched upon. Second, the understanding of flapping foils, considered as one of the most efficient cruise styles of aquatic animals, is introduced, where the effect of kinematics and the shape and flexibility of foils on generating thrust are elucidated respectively. Fast-start propulsion is always exhibited when predator behaviour occurs, and we provide an explicit introduction of corresponding zoological experiments and numerical simulations. We also provide some predictions about underwater bio-mimetic propulsion.

  5. Erythropoietin and thrombopoietin mimetics: Natural alternatives to erythrocyte and platelet disorders.

    PubMed

    Gutti, Usha; Pasupuleti, Satya Ratan; Sahu, Itishri; Kotipalli, Aneesh; Undi, Ram Babu; Kandi, Ravinder; Venakata Saladi, Raja Gopal; Gutti, Ravi Kumar

    2016-12-01

    Erythropoietin (EPO) and thrombopoietin (TPO) plays a major role in the regulation of hematopoietic development. Though, blood transfusion was the most widely used method to treat low blood count, over the years with advancements in recombinant technology and drug designing, the EPO and TPO mimetics are dominating the therapeutics industry. On the other hand, the recombinant human EPO and TPO are associated either with reduced half-life or immune reactions. The restoration of alternate medicine in recent years has the hope to overcome limitations associated with recombinant technology, to treat various disorder including blood diseases, with low to no side effects. The work in recent years on plant derived mimetics suggests a paradigm shift in the way diseases are treated. Here, we are providing a comprehensive review on the EPO and TPO recombinant counterparts and synthetic mimetics studied till date with a focus on the need for more natural alternatives. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Glycosaminoglycans (GAGs) and GAG mimetics regulate the behavior of stem cell differentiation.

    PubMed

    Wang, Mengmeng; Liu, Xiaoli; Lyu, Zhonglin; Gu, Hao; Li, Dan; Chen, Hong

    2017-02-01

    Glycosaminoglycans (GAGs) are linear sulfated polysaccharides that exist in most mammalian cells. By undergoing conjugation with various proteins, GAGs play important roles in a variety of bioactivities, including promoting stem cell differentiation. However, they have their own intrinsic disadvantages that limit their further applications for cell therapy and tissue engineering. Therefore, more and more GAG-mimetic materials have been studied as natural GAG analogs for emerging applications. This review explains the mechanism of how GAGs regulate stem cell differentiation and elaborates on the current progress of the applications of GAG-based materials on regulating stem cell differentiation. The types and applications of GAG-mimetic materials on regulating stem cell differentiation are introduced as well. Finally, the challenges and perspectives for GAGs and their mimetics in regulating stem cell differentiation are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. Healthy imperfect dark matter from effective theory of mimetic cosmological perturbations

    SciTech Connect

    Hirano, Shin'ichi; Nishi, Sakine; Kobayashi, Tsutomu, E-mail: s.hirano@rikkyo.ac.jp, E-mail: sakine@rikkyo.ac.jp, E-mail: tsutomu@rikkyo.ac.jp

    2017-07-01

    We study the stability of a recently proposed model of scalar-field matter called mimetic dark matter or imperfect dark matter. It has been known that mimetic matter with higher derivative terms suffers from gradient instabilities in scalar perturbations. To seek for an instability-free extension of imperfect dark matter, we develop an effective theory of cosmological perturbations subject to the constraint on the scalar field's kinetic term. This is done by using the unifying framework of general scalar-tensor theories based on the ADM formalism. We demonstrate that it is indeed possible to construct a model of imperfect dark matter which ismore » free from ghost and gradient instabilities. As a side remark, we also show that mimetic F (R) theory is plagued with the Ostrogradsky instability.« less

  8. Ligand selectivity of a synthetic CXCR4 mimetic peptide.

    PubMed

    Groß, Andrea; Brox, Regine; Damm, Dominik; Tschammer, Nuška; Schmidt, Barbara; Eichler, Jutta

    2015-07-15

    The chemokine receptor CXCR4 belongs to the family of seven-transmembrane G-protein coupled receptors (GPCRs). It is activated by its natural ligand SDF-1α. In addition, CXCR4, along with CCR5, serve as coreceptors during HIV-1 entry into its target cell. Recently, we introduced a CXCR4 mimetic peptide, termed CX4-M1, which presents the three extracellular loops (ECLs) of the receptor. CX4-M1 was shown to selectively bind to gp120 of X4-tropic, that is, CXCR4 using, HIV-1, as well as to peptides that present the V3-loops of these gp120 proteins. Furthermore, CX4-M1 selectively inhibits infection of cells with X4-tropic HIV-1. We have now adapted the sequence of the ECLs presented by CX4-M1 to the recently published crystal structure of CXCR4. The binding behavior, as well as the effect on HIV-1 infection, of the resulting peptide (CX4-Mc) was very similar to CX4-M1, validating retrospectively the original design of CX4-M1. A peptide presenting the ECLs of CCR5 (CR5-M), on the other hand, did neither bind to gp120 from X4-tropic HIV-1, nor did it inhibit infection of cells with X4-tropic HIV-1. Furthermore, we could show that CX4-M1, as well as CX4-Mc, but not CR5-M, are selectively recognized by anti-CXCR4 antibodies, bind to SDF-1α, and also inhibit SDF-1α signaling, extending the scope of selective functional CXCR4 mimicry through CX4-M1. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Hierachical assembly of collagen mimetic peptides into biofunctional materials

    NASA Astrophysics Data System (ADS)

    Gleaton, Jeremy W.

    Collagen is a remarkably strong and prevalent protein distributed throughout nature and as such, collagen is an ideal material for a variety of medical applications. Research efforts for the development of synthetic collagen biomaterials is an area of rapid growth. Here we present two methods for the assembly of collagen mimetic peptides (CMPs). The initial approach prompts assembly of CMPs which contain modifications for metal ion-triggered assembly. Hierarchical assembly into triple helices, followed by formation of disks via hydrophobic interactions has been demonstrated. Metal-ion mediated assembly of these disks, using iron (II)-bipyrdine interactions, has been shown to form micron-sized cages. The nature of the final structures that form depends on the number of bipyridine moieties incorporated into the CMP. These hollow spheres encapsulate a range of molecular weight fluorescently labeled dextrans. Furthermore, they demonstrate a time dependent release of contents under a variety of thermal conditions. The second approach assembles CMPs via the copper-catalyzed alkyne-azide cycloaddition (CuAAC) and the strain-promoted alkyne-azide cycloaddition (SPAAC) reactions. CMPs that incorporate the unnatural amino acids L-propargylglycine and L-azidolysine form triple helices and demonstrate higher order assembly when reacted via CuAAC. Reaction of the alkyne/azide modified CMPs under CuAAC conditions was found to produce an crosslinked 3-dimensional network. Moreover, we demonstrate that polymers, such as, PEG, can be reacted with alkyne and azide CMP triple helices via CuAAC and SPAAC. This designed covalent CMP chemistry allows for high flexibility in integrating various chemical cues, such as cell growth and differentiation within the higher order structures.

  10. Mussel-mimetic, bioadhesive polymers from plant-derived materials.

    PubMed

    Hiraishi, Noriko; Kaneko, Daisaku; Taira, Shu; Wang, Siqian; Otsuki, Masayuki; Tagami, Junji

    2015-02-01

    Mussel-mimetic, bioadhesive polymers are synthesized from plant-derived sources. The strong adhesive action is caused by interactions between the catechol groups at the end of the polymer terminal chains and the substrate surface. Here, we present a preliminary study of the adhesion properties and a discussion of the adhesion mechanism. Two bioadhesive polymers were synthesized from natural plant-derived monomers by the transesterification of: (a) caffeic acid (3,4-dihydroxycinnamic acid; DHCA) and p-coumaric acid (4-hydroxycinnamic acid; 4HCA) to produce poly(DHCA-co-4HCA); and (b) 4-dihydroxyhydrocinnamic acid (DHHCA) and 3-(3-hydroxyphenyl) propionic acid (3HPPA) to produce poly(DHHCA-co-3HPPA). Thermoplastic poly(DHCA-co-4HCA) or poly(DHHCA-co-3HPPA) was placed between glass, carbon, steel, or bovine dentin substrates, and a lap shear adhesion test was conducted to compare them using conventional cyanoacrylate glue and epoxy resin. The greatest adhesion for all tested substrates was exhibited by poly(DHHCA-co-3HPPA), followed by epoxy resin adhesive, poly(DHCA-co-4HCA), and cyanoacrylate adhesive. The adhesive strength of poly(DHHCA-co-3HPPA) was greater than 25.6 MPa for glass, 29.6 MPa for carbon, 15.7 MPa for steel, and 16.3 MPA for bovine dentin. The adhesion of poly(DHHCA-co-3HPPA) might be the strongest reported for a mussel-mimic adhesive system, and could be a feasible alternative to petroleum adhesives. © 2013 Wiley Publishing Asia Pty Ltd.

  11. An overview on antidiabetic medicinal plants having insulin mimetic property

    PubMed Central

    Patel, DK; Prasad, SK; Kumar, R; Hemalatha, S

    2012-01-01

    Diabetes mellitus is one of the common metabolic disorders acquiring around 2.8% of the world's population and is anticipated to cross 5.4% by the year 2025. Since long back herbal medicines have been the highly esteemed source of medicine therefore, they have become a growing part of modern, high-tech medicine. In view of the above aspects the present review provides profiles of plants (65 species) with hypoglycaemic properties, available through literature source from various database with proper categorization according to the parts used, mode of reduction in blood glucose (insulinomimetic or insulin secretagogues activity) and active phytoconstituents having insulin mimetics activity. From the review it was suggested that, plant showing hypoglycemic potential mainly belongs to the family Leguminoseae, Lamiaceae, Liliaceae, Cucurbitaceae, Asteraceae, Moraceae, Rosaceae and Araliaceae. The most active plants are Allium sativum, Gymnema sylvestre, Citrullus colocynthis, Trigonella foenum greacum, Momordica charantia and Ficus bengalensis. The review describes some new bioactive drugs and isolated compounds from plants such as roseoside, epigallocatechin gallate, beta-pyrazol-1-ylalanine, cinchonain Ib, leucocyandin 3-O-beta-d-galactosyl cellobioside, leucopelargonidin-3- O-alpha-L rhamnoside, glycyrrhetinic acid, dehydrotrametenolic acid, strictinin, isostrictinin, pedunculagin, epicatechin and christinin-A showing significant insulinomimetic and antidiabetic activity with more efficacy than conventional hypoglycaemic agents. Thus, from the review majorly, the antidiabetic activity of medicinal plants is attributed to the presence of polyphenols, flavonoids, terpenoids, coumarins and other constituents which show reduction in blood glucose levels. The review also discusses the management aspect of diabetes mellitus using these plants and their active principles. PMID:23569923

  12. Apolipoproteins and apolipoprotein mimetic peptides modulate phagocyte trafficking through chemotactic activity.

    PubMed

    Madenspacher, Jennifer H; Azzam, Kathleen M; Gong, Wanghua; Gowdy, Kymberly M; Vitek, Michael P; Laskowitz, Daniel T; Remaley, Alan T; Wang, Ji Ming; Fessler, Michael B

    2012-12-21

    The plasma lipoprotein-associated apolipoproteins (apo) A-I and apoE have well described anti-inflammatory actions in the cardiovascular system, and mimetic peptides that retain these properties have been designed as therapeutics. The anti-inflammatory mechanisms of apolipoprotein mimetics, however, are incompletely defined. Whether circulating apolipoproteins and their mimetics regulate innate immune responses at mucosal surfaces, sites where transvascular emigration of leukocytes is required during inflammation, remains unclear. Herein, we report that Apoai(-/-) and Apoe(-/-) mice display enhanced recruitment of neutrophils to the airspace in response to both inhaled lipopolysaccharide and direct airway inoculation with CXCL1. Conversely, treatment with apoA-I (L-4F) or apoE (COG1410) mimetic peptides reduces airway neutrophilia. We identify suppression of CXCR2-directed chemotaxis as a mechanism underlying the apolipoprotein effect. Pursuing the possibility that L-4F might suppress chemotaxis through heterologous desensitization, we confirmed that L-4F itself induces chemotaxis of human PMNs and monocytes. L-4F, however, fails to induce a calcium flux. Further exploring structure-function relationships, we studied the alternate apoA-I mimetic L-37pA, a bihelical analog of L-4F with two Leu-Phe substitutions. We find that L-37pA induces calcium and chemotaxis through formyl peptide receptor (FPR)2/ALX, whereas its D-stereoisomer (i.e. D-37pA) blocks L-37pA signaling and induces chemotaxis but not calcium flux through an unidentified receptor. Taken together, apolipoprotein mimetic peptides are novel chemotactic agents that possess complex structure-activity relationships to multiple receptors, displaying anti-inflammatory efficacy against innate immune responses in the airway.

  13. Apolipoproteins and Apolipoprotein Mimetic Peptides Modulate Phagocyte Trafficking through Chemotactic Activity*

    PubMed Central

    Madenspacher, Jennifer H.; Azzam, Kathleen M.; Gong, Wanghua; Gowdy, Kymberly M.; Vitek, Michael P.; Laskowitz, Daniel T.; Remaley, Alan T.; Wang, Ji Ming; Fessler, Michael B.

    2012-01-01

    The plasma lipoprotein-associated apolipoproteins (apo) A-I and apoE have well described anti-inflammatory actions in the cardiovascular system, and mimetic peptides that retain these properties have been designed as therapeutics. The anti-inflammatory mechanisms of apolipoprotein mimetics, however, are incompletely defined. Whether circulating apolipoproteins and their mimetics regulate innate immune responses at mucosal surfaces, sites where transvascular emigration of leukocytes is required during inflammation, remains unclear. Herein, we report that Apoai−/− and Apoe−/− mice display enhanced recruitment of neutrophils to the airspace in response to both inhaled lipopolysaccharide and direct airway inoculation with CXCL1. Conversely, treatment with apoA-I (L-4F) or apoE (COG1410) mimetic peptides reduces airway neutrophilia. We identify suppression of CXCR2-directed chemotaxis as a mechanism underlying the apolipoprotein effect. Pursuing the possibility that L-4F might suppress chemotaxis through heterologous desensitization, we confirmed that L-4F itself induces chemotaxis of human PMNs and monocytes. L-4F, however, fails to induce a calcium flux. Further exploring structure-function relationships, we studied the alternate apoA-I mimetic L-37pA, a bihelical analog of L-4F with two Leu-Phe substitutions. We find that L-37pA induces calcium and chemotaxis through formyl peptide receptor (FPR)2/ALX, whereas its D-stereoisomer (i.e. D-37pA) blocks L-37pA signaling and induces chemotaxis but not calcium flux through an unidentified receptor. Taken together, apolipoprotein mimetic peptides are novel chemotactic agents that possess complex structure-activity relationships to multiple receptors, displaying anti-inflammatory efficacy against innate immune responses in the airway. PMID:23118226

  14. Novel SMAC-mimetics synergistically stimulate melanoma cell death in combination with TRAIL and Bortezomib.

    PubMed

    Lecis, D; Drago, C; Manzoni, L; Seneci, P; Scolastico, C; Mastrangelo, E; Bolognesi, M; Anichini, A; Kashkar, H; Walczak, H; Delia, D

    2010-06-08

    XIAP (X-linked inhibitor of apoptosis protein) is an anti-apoptotic protein exerting its activity by binding and suppressing caspases. As XIAP is overexpressed in several tumours, in which it apparently contributes to chemoresistance, and because its activity in vivo is antagonised by second mitochondria-derived activator of caspase (SMAC)/direct inhibitor of apoptosis-binding protein with low pI, small molecules mimicking SMAC (so called SMAC-mimetics) can potentially overcome tumour resistance by promoting apoptosis. Three homodimeric compounds were synthesised tethering a monomeric SMAC-mimetic with different linkers and their affinity binding for the baculoviral inhibitor repeats domains of XIAP measured by fluorescent polarisation assay. The apoptotic activity of these molecules, alone or in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and/or Bortezomib, was tested in melanoma cell lines by MTT viability assays and western blot analysis of activated caspases. We show that in melanoma cell lines, which are typically resistant to chemotherapeutic agents, XIAP knock-down sensitises cells to TRAIL treatment in vitro, also favouring the accumulation of cleaved caspase-8. We also describe a new series of 4-substituted azabicyclo[5.3.0]alkane monomeric and dimeric SMAC-mimetics that target various members of the IAP family and powerfully synergise at submicromolar concentrations with TRAIL in inducing cell death. Finally, we show that the simultaneous administration of newly developed SMAC-mimetics with Bortezomib potently triggers apoptosis in a melanoma cell line resistant to the combined effect of SMAC-mimetics and TRAIL. Hence, the newly developed SMAC-mimetics effectively synergise with TRAIL and Bortezomib in inducing cell death. These findings warrant further preclinical studies in vivo to verify the anticancer effectiveness of the combination of these agents.

  15. Dormancy as exaptation to protect mimetic seeds against deterioration before dispersal.

    PubMed

    Brancalion, Pedro H S; Novembre, Ana D L C; Rodrigues, Ricardo R; Marcos Filho, Júlio

    2010-06-01

    Mimetic seeds simulate the appearance of fleshy fruits and arilled seeds without producing nutritive tissues as a reward for seed dispersers. In this strategy of seed dispersal, seeds may remain attached to the mother plant for long periods after maturity, increasing their availability to naïve seed dispersers. The hypothesis that seed coat impermeability in many tropical Fabaceae with mimetic seeds serves as an exaptation to protect the seeds from deterioration and rotting while awaiting dispersal was investigated. Seed coat impermeability was evaluated in five mimetic-seeded species of tropical Fabaceae in south-eastern Brazil (Abarema langsdorffii, Abrus precatorius, Adenanthera pavonina, Erythrina velutina and Ormosia arborea) and in Erythrina speciosa, a 'basal' species in its genus, which has monochromatic brown seeds and no mimetic displays. Seed hardness was evaluated as a defence against accelerated ageing (humid chamber at 41 degrees C for 144 h). Seed development and physiological potential of O. arborea was evaluated and the effect of holding mature seeds in pods on the mother plant in the field for a period of 1 year under humid tropical conditions was compared with seeds stored under controlled conditions (15 degrees C and 40 % relative air humidity). All five mimetic-seeded species, and E. speciosa, showed strong coat impermeability, which protected the seeds against deterioration in accelerated ageing. Most O. arborea seeds only became dormant 2 months after pod dehiscence. Germination of seeds after 1 year on the plant in a humid tropical climate was 56 %, compared with 80 % for seeds stored in controlled conditions (15 degrees C, 45 % relative humidity). Seedling shoot length after 1 year did not differ between seed sources. Dormancy acts in mimetic-seeded species as an exaptation to reduce seed deterioration, allowing an increase in their effective dispersal period and mitigating the losses incurred by low removal rates by naïve avian

  16. Max Bergmann lecture Protein epitope mimetics in the age of structural vaccinology‡

    PubMed Central

    Robinson, John A

    2013-01-01

    This review highlights the growing importance of protein epitope mimetics in the discovery of new biologically active molecules and their potential applications in drug and vaccine research. The focus is on folded β-hairpin mimetics, which are designed to mimic β-hairpin motifs in biologically important peptides and proteins. An ever-growing number of protein crystal structures reveal how β-hairpin motifs often play key roles in protein–protein and protein–nucleic acid interactions. This review illustrates how using protein structures as a starting point for small-molecule mimetic design can provide novel ligands as protein–protein interaction inhibitors, as protease inhibitors, and as ligands for chemokine receptors and folded RNA targets, as well as novel antibiotics to combat the growing health threat posed by the emergence of antibiotic-resistant bacteria. The β-hairpin antibiotics are shown to target a β-barrel outer membrane protein (LptD) in Pseudomonas sp., which is essential for the biogenesis of the outer cell membrane. Another exciting prospect is that protein epitope mimetics will be of increasing importance in synthetic vaccine design, in the emerging field of structural vaccinology. Crystal structures of protective antibodies bound to their pathogen-derived epitopes provide an ideal starting point for the design of synthetic epitope mimetics. The mimetics can be delivered to the immune system in a highly immunogenic format on the surface of synthetic virus-like particles. The scientific challenges in molecular design remain great, but the potential significance of success in this area is even greater. Copyright © 2013 European Peptide Society and John Wiley & Sons, Ltd. PMID:23349031

  17. LRIG1 modulates cancer cell sensitivity to Smac mimetics by regulating TNFα expression and receptor tyrosine kinase signaling.

    PubMed

    Bai, Longchuan; McEachern, Donna; Yang, Chao-Yie; Lu, Jianfeng; Sun, Haiying; Wang, Shaomeng

    2012-03-01

    Smac mimetics block inhibitor of apoptosis proteins to trigger TNFα-dependent apoptosis in cancer cells. However, only a small subset of cancer cells seem to be sensitive to Smac mimetics and even sensitive cells can develop resistance. Herein, we elucidated mechanisms underlying the intrinsic and acquired resistance of cancer cells to Smac mimetics. In vitro and in vivo investigations revealed that the expression of the cell surface protein LRIG1, a negative regulator of receptor tyrosine kinases (RTK), is downregulated in resistant derivatives of breast cancer cells sensitive to Smac mimetics. RNA interference-mediated downregulation of LRIG1 markedly attenuated the growth inhibitory activity of the Smac mimetic SM-164 in drug-sensitive breast and ovarian cancer cells. Furthermore, LRIG1 downregulation attenuated TNFα gene expression induced by Smac mimetics and increased the activity of multiple RTKs, including c-Met and Ron. The multitargeted tyrosine kinase inhibitors Crizotinib and GSK1363089 greatly enhanced the anticancer activity of SM-164 in all resistant cell derivatives, with the combination of SM-164 and GSK1363089 also completely inhibiting the outgrowth of resistant tumors in vivo. Together, our findings show that both upregulation of RTK signaling and attenuated TNFα expression caused by LRIG1 downregulation confers resistance to Smac mimetics, with implications for a rational combination strategy.

  18. The Representation of Reality in Teaching: A "Mimetic Didactic" Perspective on Examples in Plenary Talk

    ERIC Educational Resources Information Center

    Willbergh, Ilmi

    2017-01-01

    Using an observation study in Norwegian lower-secondary school classrooms this paper explores how subject matter and students' real-world experiences are linked within the use of examples in teaching. The theory of "mimetic didactics" claims that giving students the possibility to interpret examples as both subject matter and something…

  19. A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin

    PubMed Central

    Lee, Eugene K; Jinesh G, Goodwin; Laing, Naomi M; Choi, Woonyoung; McConkey, David J; Kamat, Ashish M

    2013-01-01

    Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. However, despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Using a panel of 10 urothelial cancer cell lines, we exposed them to a combination of gemcitabine, cisplatin, and a Smac mimetic. Sensitivity was determined using a DNA fragmentation assay. We determined that three cell lines (UMUC-3, UMUC-13, and RT4v6) were considered sensitive to the combination of gemcitabine and cisplatin and an additional three cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, and UMUC-18). We next explored the constitutive expression of selected members of the IAP family (XIAP, cIAP-1, cIAP-2, and Survivin), the BCL family (BCL-2, BCLXL, and BAX) and Smac using gene expression profiling and western blotting. We determined that RNA and protein expression of SMAC, selected members of the IAP family and members of the BCL family did not correlate to drug sensitivity. Lastly, using an in vivo mouse model, we determined that treatment with the Smac mimetic in combination with gemcitabine and cisplatin resulted in increased apoptosis, decreased microvessel density and decreased cellular proliferation. This novel treatment strategy may be effective in patients with advanced urothelial carcinoma and warrants further investigation. PMID:23792592

  20. A Smac mimetic augments the response of urothelial cancer cells to gemcitabine and cisplatin.

    PubMed

    Lee, Eugene K; Jinesh G, Goodwin; Laing, Naomi M; Choi, Woonyoung; McConkey, David J; Kamat, Ashish M

    2013-09-01

    Cisplatin-based chemotherapy is considered the gold standard for patients with advanced bladder cancer. However, despite initial response, many patients will relapse; therefore, novel salvage treatment strategies are desperately needed. Herein, we studied a mechanism based treatment combination using a Smac mimetic with standard chemotherapy. Using a panel of 10 urothelial cancer cell lines, we exposed them to a combination of gemcitabine, cisplatin, and a Smac mimetic. Sensitivity was determined using a DNA fragmentation assay. We determined that three cell lines (UMUC-3, UMUC-13, and RT4v6) were considered sensitive to the combination of gemcitabine and cisplatin and an additional three cell lines were sensitized to gemcitabine and cisplatin with the addition of the Smac mimetic (UMUC-6, UMUC-12, and UMUC-18). We next explored the constitutive expression of selected members of the IAP family (XIAP, cIAP-1, cIAP-2, and Survivin), the BCL family (BCL-2, BCLXL, and BAX) and Smac using gene expression profiling and western blotting. We determined that RNA and protein expression of SMAC, selected members of the IAP family and members of the BCL family did not correlate to drug sensitivity. Lastly, using an in vivo mouse model, we determined that treatment with the Smac mimetic in combination with gemcitabine and cisplatin resulted in increased apoptosis, decreased microvessel density and decreased cellular proliferation. This novel treatment strategy may be effective in patients with advanced urothelial carcinoma and warrants further investigation.

  1. The two faces of mimetic Horndeski gravity: disformal transformations and Lagrange multiplier

    SciTech Connect

    Arroja, Frederico; Bartolo, Nicola; Karmakar, Purnendu

    2015-09-01

    We show that very general scalar-tensor theories of gravity (including, e.g., Horndeski models) are generically invariant under disformal transformations. However there is a special subset, when the transformation is not invertible, that yields new equations of motion which are a generalization of the so-called 'mimetic' dark matter theory recently introduced by Chamsedinne and Mukhanov. These conclusions hold true irrespective of whether the scalar field in the action of the assumed scalar-tensor theory of gravity is the same or different than the scalar field involved in the transformation. The new equations of motion for our general mimetic theory can also bemore » derived from an action containing an additional Lagrange multiplier field. The general mimetic scalar-tensor theory has the same number of derivatives in the equations of motion as the original scalar-tensor theory. As an application we show that the simplest mimetic scalar-tensor model is able to mimic the cosmological background of a flat FLRW model with a barotropic perfect fluid with any constant equation of state.« less

  2. The relationship between mimetic imperfection and phenotypic variation in insect colour patterns.

    PubMed Central

    Holloway, Graham; Gilbert, Francis; Brandt, Amoret

    2002-01-01

    Many hoverflies (Syrphidae) mimic wasps or bees through colour or behavioural adaptations. The relationship between phenotypic variation in colour pattern and mimetic perfection (as determined by pigeons) was investigated in three species of Müllerian mimics (Vespula spp.) and 10 Batesian hoverfly mimics, plus two non-mimetic species of flies. Four predictions were tested: (i) Batesian mimics might be imperfect because they are in the process of evolving towards perfection, hence there should be a positive relationship between variation and imperfection; (ii) some Batesian mimics are imperfect because they do not have the appropriate genetic variation to improve and have evolved to be as good as possible, hence there should be no differences between species, all displaying a low level of variation; (iii) very common hoverflies should show the highest levels of variation because they outnumber their models, resulting in high predation and a breakdown in the mimetic relationship; and (iv) social wasps (Vespula) have such a powerful defence that anything resembling a wasp, both Müllerian and perfect Batesian mimics, would be avoided, resulting in relaxed selection and high variance. Poor mimics may still evolve to resemble wasps as well as possible and display lower levels of variation. The data only provided support for the fourth prediction. The Müllerian mimics, one of the most perfect Batesian mimics, and the non-mimetic flies displayed much higher levels of variation than the other species of Batesian mimics. PMID:11886630

  3. Student-Driven Design of Peptide Mimetics: Microwave-Assisted Synthesis of Peptoid Oligomers

    ERIC Educational Resources Information Center

    Pohl, Nicola L. B.; Kirshenbaum, Kent; Yoo, Barney; Schulz, Nathan; Zea, Corbin J.; Streff, Jennifer M.; Schwarz, Kimberly L.

    2011-01-01

    An experiment for the undergraduate organic laboratory is described in which peptide mimetic oligomers called "peptoids" are built stepwise on a solid-phase resin. Students employ two modern strategies to facilitate rapid multistep syntheses: solid-phase techniques to obviate the need for intermediate purifications and microwave irradiation to…

  4. Smac mimetics in combination with TRAIL selectively target cancer stem cells in nasopharyngeal carcinoma.

    PubMed

    Wu, Man-Si; Wang, Guang-Feng; Zhao, Zhi-Qiang; Liang, Yi; Wang, Heng-Bang; Wu, Miao-Yi; Min, Ping; Chen, Li-zhen; Feng, Qi-Sheng; Bei, Jin-Xin; Zeng, Yi-Xin; Yang, Dajun

    2013-09-01

    Nasopharyngeal carcinoma is a common malignancy in Southern China. After radiotherapy and chemotherapy, a considerable proportion of patients with nasopharyngeal carcinoma suffered tumor relapse and metastasis. Cancer stem cells (CSC) have been shown with resistance against therapies and thus considered as the initiator of recurrence and metastasis in tumors, where the antiapoptotic property of CSCs play an important role. Smac/DIABLO is an inverse regulator for the inhibitors of apoptosis protein family (IAP), which have been involved in apoptosis. Here, the effects of Smac mimetics on the CSCs of nasopharyngeal carcinoma were studied both in vitro and in vivo, using two clones of nasopharyngeal carcinoma cell line CNE2 as models. We found that one of the clones, S18, had CSC-like properties and IAPs were overexpressed. The combination of Smac mimetics and TNF-related apoptosis-inducing ligand (TRAIL) can reduce the percentage of SP cells and inhibit the colony- and sphere-forming abilities of S18 cells, indicating their ability to attenuate the CSCs. Moreover, in a nasopharyngeal carcinoma xenograft model, the administration of Smac mimetics in combination with TRAIL also led to the elimination of nasopharyngeal carcinoma stem cells. Furthermore, the Smac mimetics in combination with TRAIL induced the degradation of cIAP1 and XIAP and thus induced apoptosis in vitro and in vivo. Taken together, our data show that Smac mimetics exerted an antitumor effect on nasopharyngeal carcinoma cancer stem cells, and this combination treatment should be considered as a promising strategy for the treatment of nasopharyngeal carcinoma.

  5. Smac-mimetic-induced epithelial cell death reduces the growth of renal cysts.

    PubMed

    Fan, Lucy X; Zhou, Xia; Sweeney, William E; Wallace, Darren P; Avner, Ellis D; Grantham, Jared J; Li, Xiaogang

    2013-12-01

    Past efforts to pharmacologically disrupt the development and growth of renal cystic lesions focused primarily on normalizing the activity of a specific signaling molecule, but the effects of stimulating apoptosis in the proliferating epithelial cells have not been well studied. Although benign, ADPKD renal cysts created by the sustained proliferation of epithelial cells resemble tumors, and malignant cell death can be achieved by cotreatment with TNF-α and a mimetic of second mitochondria-derived activator of caspase (Smac). Notably, TNF-α accumulates to high levels in ADPKD cyst fluid. Here, we report that an Smac-mimetic selectively induces TNF-α-dependent cystic renal epithelial cell death, leading to the removal of cystic epithelial cells from renal tissues and delaying cyst formation. In vitro, a Smac-mimetic (GT13072) induced the degradation of cIAP1 that is required but not sufficient for cell death. Cotreatment with TNF-α augmented the formation and activation of the RIPK1-dependent death complex and the degradation and cleavage of FLIP, an inhibitor of caspase-8, in renal cystic epithelial cells. This approach produced death specifically in Pkd1 mutant epithelial cells, with no effect on normal renal epithelial cells. Moreover, treatment with the Smac-mimetic slowed cyst and kidney enlargement and preserved renal function in two genetic strains of mice with Pkd1 mutations. Thus, our mechanistic data characterize an apoptotic pathway, activated by the selective synergy of an Smac-mimetic and TNF-α in renal cyst fluid, that attenuates cyst development, providing an innovative translational platform for the rational development of novel therapeutics for ADPKD.

  6. A Platelet-Mimetic Paradigm for Metastasis-Targeted Nanomedicine Platforms

    PubMed Central

    Modery-Pawlowski, Christa L.; Master, Alyssa M.; Pan, Victor; Howard, Gregory; Gupta, Anirban Sen

    2013-01-01

    There is compelling evidence that beyond their traditional role in hemostasis and thrombosis, platelets play a significant role in mediating hematologic mechanisms of tumor metastasis by directly and indirectly interacting with pro-metastatic cancer cells. With this rationale, we hypothesized that platelets can be an effective paradigm to develop nanomedicine platforms that utilize platelet-mimetic interaction mechanisms for targeted diagnosis and therapy of metastatic cancer cells. Here we report on our investigation of the development of nanoconstructs that interact with metastatic cancer cells via platelet-mimetic heteromultivalent ligand-receptor pathways. For our studies, pro-metastatic human breast cancer cell line MDA-MB-231 was studied for its surface expression of platelet-interactive receptors, in comparison to another low-metastatic human breast cancer cell line, MCF-7. Certain platelet-interactive receptors were found to be significantly over-expressed on the MDA-MB-231 cells and these cells showed significantly enhanced binding interactions with active platelets compared to MCF-7 cells. Based upon these observations, two specific receptor interactions were selected and corresponding ligands were engineered onto the surface of liposomes as model nanoconstructs, to enable platelet-mimetic binding to the cancer cells. Our model platelet-mimetic liposomal constructs showed enhanced targeting and attachment of MDA-MB-231 cells compared to the MCF-7 cells. These results demonstrate the promise of utilizing platelet-mimetic constructs in modifying nanovehicle constructs for metastasis-targeted drug as well as modifying surfaces for ex-vivo cell enrichment diagnostic technologies. PMID:23360320

  7. Social variables exert selective pressures in the evolution and form of primate mimetic musculature.

    PubMed

    Burrows, Anne M; Li, Ly; Waller, Bridget M; Micheletta, Jerome

    2016-04-01

    Mammals use their faces in social interactions more so than any other vertebrates. Primates are an extreme among most mammals in their complex, direct, lifelong social interactions and their frequent use of facial displays is a means of proximate visual communication with conspecifics. The available repertoire of facial displays is primarily controlled by mimetic musculature, the muscles that move the face. The form of these muscles is, in turn, limited by and influenced by phylogenetic inertia but here we use examples, both morphological and physiological, to illustrate the influence that social variables may exert on the evolution and form of mimetic musculature among primates. Ecomorphology is concerned with the adaptive responses of morphology to various ecological variables such as diet, foliage density, predation pressures, and time of day activity. We present evidence that social variables also exert selective pressures on morphology, specifically using mimetic muscles among primates as an example. Social variables include group size, dominance 'style', and mating systems. We present two case studies to illustrate the potential influence of social behavior on adaptive morphology of mimetic musculature in primates: (1) gross morphology of the mimetic muscles around the external ear in closely related species of macaque (Macaca mulatta and Macaca nigra) characterized by varying dominance styles and (2) comparative physiology of the orbicularis oris muscle among select ape species. This muscle is used in both facial displays/expressions and in vocalizations/human speech. We present qualitative observations of myosin fiber-type distribution in this muscle of siamang (Symphalangus syndactylus), chimpanzee (Pan troglodytes), and human to demonstrate the potential influence of visual and auditory communication on muscle physiology. In sum, ecomorphologists should be aware of social selective pressures as well as ecological ones, and that observed morphology might

  8. Tunable elastin-mimetic multiblock hybrid copolymers for biomedical applications

    NASA Astrophysics Data System (ADS)

    Grieshaber, Sarah Elizabeth

    Elastin-mimetic hybrid polymers (EMHPs) have been developed to capture the multiblock molecular architecture of tropoelastin, allowing tunability in chemical, structural, biological, and mechanical properties. Multiblock EMHPs containing flexible synthetic segments were first synthesized via step growth polymerization of diazido-poly(ethylene glycol) (PEG) and alkyne-terminated AKA3KA (K = lysine, A = alanine) (AK2) peptide employing copper (I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC, or orthogonal click chemistry). Covalent crosslinking of the EMHPs with hexamethylene diisocyanate (HMDI) through the lysine residues in the peptide domain afforded an elastomeric hydrogel (xEMHP) with a compressive modulus of 0.12 +/- 0.018 MPa when hydrated. xEMHPs exhibited minimal cytotoxicity to primary porcine vocal fold fibroblasts. The modular nature of the synthesis allowed facile adjustment of the peptide sequence to modulate the structural and the biological properties of EMHPs. Thus, EMHPs containing integrin-binding peptides were constructed using di-azido-PEG and an alkyne-terminated AK2 peptide with a terminal, integrin-binding GRGDSP domain via the step growth click coupling reaction. Hydrogels formed by covalent crosslinking of the RGD-containing EMHPs had a compressive modulus of 1.06 +/- 0.1MPa when hydrated. Neonatal human dermal fibroblasts (NHDFs) were able to adhere to the hydrogels within 1 h, and to spread and develop F-actin filaments 24 h post seeding. NHDF proliferation was only observed on hydrogels containing RGD domains, demonstrating the importance of integrin engagement for cell growth and the potential use of these EMHPs as tissue engineering scaffolds. The tunability of the EMHP system was further investigated by development of self-assembling, pH-responsive multiblock polymers composed of alternating domains of poly(acrylic acid) (PAA) and a peptide derived from the hydrophobic domains of elastin with the sequence (VPGVG)2 (VG2). The

  9. What kind of signals do mimetic tiger moths send? A phylogenetic test of wasp mimicry systems (Lepidoptera: Arctiidae: Euchromiini).

    PubMed

    Simmons, Rebecca B; Weller, Susan J

    2002-05-22

    Mimicry has been examined in field and laboratory studies of butterflies and its evolutionary dynamics have been explored in computer simulations. Phylogenetic studies examining the evolution of mimicry, however, are rare. Here, the phylogeny of wasp-mimicking tiger moths, the Sphecosoma group, was used to test evolutionary predictions of computer simulations of conventional Müllerian mimicry and quasi-Batesian mimicry dynamics. We examined whether mimetic traits evolved individually, or as suites of characters, using concentrated change tests. The phylogeny of these moth mimics revealed that individual mimetic characters were conserved, as are the three mimetic wasp forms: yellow Polybia, black Polybia and Parachartergus mimetic types. This finding was consistent with a 'supergene' control of linked loci and the Nicholson two-step model of mimicry evolution. We also used a modified permutation-tail probability approach to examine the rate of mimetic-type evolution. The observed topology, hypothetical Müllerian and Batesian scenarios, and 1000 random trees were compared using Kishino-Hasegawa tests. The observed phylogeny was more consistent with the predicted Müllerian distribution of mimetic traits than with that of a quasi-Batesian scenario. We suggest that the range of discriminatory abilities of the predator community plays a key role in shaping mimicry dynamics.

  10. Vacancy-Engineered Nanoceria: Enzyme Mimetic Hotspots for the Degradation of Nerve Agents.

    PubMed

    Vernekar, Amit A; Das, Tandrila; Mugesh, Govindasamy

    2016-01-22

    Organophosphorus-based nerve agents, such as paraoxon, parathion, and malathion, inhibit acetylcholinesterase, which results in paralysis, respiratory failure, and death. Bacteria are known to use the enzyme phosphotriesterase (PTE) to break down these compounds. In this work, we designed vacancy-engineered nanoceria (VE CeO2 NPs) as PTE mimetic hotspots for the rapid degradation of nerve agents. We observed that the hydrolytic effect of the nanomaterial is due to the synergistic activity between both Ce(3+) and Ce(4+) ions located in the active site-like hotspots. Furthermore, the catalysis by nanoceria overcomes the product inhibition generally observed for PTE and small molecule-based PTE mimetics. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. The controlled release of insulin-mimetic metal ions by the multifunction of chitosan.

    PubMed

    Kofuji, Kyoko; Qian, Chun-Jun; Murata, Yoshifumi; Kawashima, Susumu

    2005-06-01

    Vanadium, which is an insulin-mimetic metal ion, was efficiently adsorbed on chitosan (CS). The adsorption of vanadium on CS was affected by the vanadium/CS ratio and the initial concentration of vanadium in preparative medium under constant pH condition. The vanadium-CS complex was able to control vanadium release. Moreover, a consistent control of vanadium release was achieved by incorporation of the vanadium-CS complex into a CS gel. After implantation of the CS gel retaining the vanadium-CS complex into diabetic mice, insulin-mimetic efficacy was confirmed by observation of a steady reduction in blood glucose levels. The sustained vanadium release also contributed to minimization of the side-effects. Thus, CS gel retaining the vanadium-CS complex appears promising as a vehicle for vanadium with long-term action and a low toxicity leading to its clinical use.

  12. Mimetic Theory for Cell-Centered Lagrangian Finite Volume Formulation on General Unstructured Grids

    SciTech Connect

    Sambasivan, Shiv Kumar; Shashkov, Mikhail J.; Burton, Donald E.

    2012-07-19

    A finite volume cell-centered Lagrangian scheme for solving large deformation problems is constructed based on the hypo-elastic model and using the mimetic theory. Rigorous analysis in the context of gas and solid dynamics, and arbitrary polygonal meshes, is presented to demonstrate the ability of cell-centered schemes in mimicking the continuum properties and principles at the discrete level. A new mimetic formulation based gradient evaluation technique and physics-based, frame independent and symmetry preserving slope limiters are proposed. Furthermore, a physically consistent dissipation model is employed which is both robust and inexpensive to implement. The cell-centered scheme along with these additional newmore » features are applied to solve solids undergoing elasto-plastic deformation.« less

  13. Smac mimetics and type II interferon synergistically induce necroptosis in various cancer cell lines.

    PubMed

    Cekay, Michael John; Roesler, Stefanie; Frank, Tanja; Knuth, Anne-Kathrin; Eckhardt, Ines; Fulda, Simone

    2017-12-01

    Since cancer cells often evade apoptosis, induction of necroptosis as another mode of programmed cell death is considered a promising therapeutic alternative. Here, we identify a novel synergistic interaction of Smac mimetics that antagonize x-linked Inhibitor of Apoptosis (XIAP), cellular Inhibitor of Apoptosis (cIAP) 1 and 2 with interferon (IFN)γ to induce necroptosis in apoptosis-resistant cancer cells in which caspase activation is blocked. This synergism is confirmed by calculation of combination indices (CIs) and found in both solid and hematological cancer cell lines as well as for different Smac mimetics (i.e. BV6, Birinapant), pointing to a broader relevance. Importantly, individual genetic knockdown of key components of necroptosis signaling, i.e. receptor-interacting protein (RIP) 1, RIP3 or mixed lineage kinase domain-like pseudokinase (MLKL), significantly protects from BV6/IFNγ-induced cell death. Similarly, pharmacological inhibitors of RIP1 (necrostatin-1(Nec-1)), RIP3 (GSK'872) or MLKL (necrosulfonamide (NSA)) significantly reduce BV6/IFNγ-stimulated cell death. Of note, IFN-regulatory factor (IRF)1 is required for BV6/IFNγ-mediated necroptosis, as IRF1 silencing provides protection from cell death. By comparison, antibodies blocking tumor necrosis factor (TNF)α, TNF-related apoptosis-inducing ligand (TRAIL) or CD95 ligand fail to inhibit BV6/IFNγ-induced cell death, pointing to a mechanism independently of death receptor ligands. This is the first report showing that Smac mimetics synergize with IFNγ to trigger necroptosis in apoptosis-resistant cancer cells with important implications for Smac mimetic-based strategies for the treatment of cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Late-time cosmological approach in mimetic f( R, T) gravity

    NASA Astrophysics Data System (ADS)

    Baffou, E. H.; Houndjo, M. J. S.; Hamani-Daouda, M.; Alvarenga, F. G.

    2017-10-01

    In this paper, we investigate the late-time cosmic acceleration in mimetic f( R, T) gravity with the Lagrange multiplier and potential in a Universe containing, besides radiation and dark energy, a self-interacting (collisional) matter. We obtain through the modified Friedmann equations the main equation that can describe the cosmological evolution. Then, with several models from Q(z) and the well-known particular model f( R, T), we perform an analysis of the late-time evolution. We examine the behavior of the Hubble parameter, the dark energy equation of state and the total effective equation of state and in each case we compare the resulting picture with the non-collisional matter (assumed as dust) and also with the collisional matter in mimetic f( R, T) gravity. The results obtained are in good agreement with the observational data and show that in the presence of the collisional matter the dark energy oscillations in mimetic f( R, T) gravity can be damped.

  15. Activity of Potent and Selective Host Defense Peptide Mimetics in Mouse Models of Oral Candidiasis

    PubMed Central

    Ryan, Lisa K.; Freeman, Katie B.; Masso-Silva, Jorge A.; Falkovsky, Klaudia; Aloyouny, Ashwag; Markowitz, Kenneth; Hise, Amy G.; Fatahzadeh, Mahnaz; Scott, Richard W.

    2014-01-01

    There is a strong need for new broadly active antifungal agents for the treatment of oral candidiasis that not only are active against many species of Candida, including drug-resistant strains, but also evade microbial countermeasures which may lead to resistance. Host defense peptides (HDPs) can provide a foundation for the development of such agents. Toward this end, we have developed fully synthetic, small-molecule, nonpeptide mimetics of the HDPs that improve safety and other pharmaceutical properties. Here we describe the identification of several HDP mimetics that are broadly active against C. albicans and other species of Candida, rapidly fungicidal, and active against yeast and hyphal cultures and that exhibit low cytotoxicity for mammalian cells. Importantly, specificity for Candida over commensal bacteria was also evident, thereby minimizing potential damage to the endogenous microbiome which otherwise could favor fungal overgrowth. Three compounds were tested as topical agents in two different mouse models of oral candidiasis and were found to be highly active. Following single-dose administrations, total Candida burdens in tongues of infected animals were reduced up to three logs. These studies highlight the potential of HDP mimetics as a new tool in the antifungal arsenal for the treatment of oral candidiasis. PMID:24752272

  16. On the selectivity of superoxide dismutase mimetics and its importance in pharmacological studies

    PubMed Central

    Muscoli, Carolina; Cuzzocrea, Salvatore; Riley, Dennis P; Zweier, Jay L; Thiemermann, Christoph; Wang, Zhi-Qiang; Salvemini, Daniela

    2003-01-01

    The list of pathophysiological conditions associated with the overproduction of superoxide expands every day. Much of the knowledge compiled on the role of this radical in disease has been gathered using the native superoxide dismutase enzyme and, more recently, by the use of superoxide dismutase knockout models or transgenic models that overexpress the various isoforms of the enzyme. Although the native enzyme has shown promising anti-inflammatory properties in both preclinical and clinical studies, there were drawbacks and issues associated with its use as a therapeutic agent and pharmacological tool. Based on the concept that removal of superoxide modulates the course of inflammation, synthetic, low-molecular-weight mimetics of the superoxide dismutase enzymes that could overcome some of the limitations associated with the use of the native enzyme have been designed. In this review, we will discuss the advances made using various superoxide dismutase mimetics that led to the proposal that superoxide (and/or the product of its interaction with nitric oxide, peroxynitrite) is an important mediator of inflammation, and to the conclusion that superoxide dismutase mimetics can be utilized as therapeutic agents in diseases of various etiologies. The importance of the selectivity of such compounds in pharmacological studies will be discussed. PMID:14522841

  17. The reconstruction of f(ϕ)R and mimetic gravity from viable slow-roll inflation

    NASA Astrophysics Data System (ADS)

    Odintsov, S. D.; Oikonomou, V. K.

    2018-04-01

    In this work, we extend the bottom-up reconstruction framework of F (R) gravity to other modified gravities, and in particular for f (ϕ) R and mimetic F (R) gravities. We investigate which are the important conditions in order for the method to work, and we study several viable cosmological evolutions, focusing on the inflationary era. Particularly, for the f (ϕ) R theory case, we specify the functional form of the Hubble rate and of the scalar-to-tensor ratio as a function of the e-foldings number and accordingly, the rest of the physical quantities and also the slow-roll and the corresponding observational indices can be calculated. The same method is applied in the mimetic F (R) gravity case, and in both cases we thoroughly analyze the resulting free parameter space, in order to show that the viability of the models presented is guaranteed and secondly that there is a wide range of values of the free parameters for which the viability of the models occurs. In addition, the reconstruction method is also studied in the context of mimetic F (R) = R gravity. As we demonstrate, the resulting theory is viable, and also in this case, only the scalar-to-tensor ratio needs to be specified, since the rest follow from this condition. Finally, we discuss in brief how the reconstruction method could function for other modified gravities.

  18. Lipid A Mimetics are Potent Adjuvants for an Intranasal Pneumonic Plague Vaccine

    PubMed Central

    Airhart, Christina L.; Rohde, Harold N.; Hovde, Carolyn J.; Bohach, Gregory A.; Deobald, Claudia F.; Lee, Stephen S.; Minnich, Scott A.

    2008-01-01

    An effective intranasal (i.n.) vaccine against pneumonic plague was developed. The formulation employed two synthetic lipid A mimetics as adjuvant combined with Yersinia pestis-derived V- and F1- protective antigens. The two nontoxic lipid A mimetics, classed as amino-alkyl glucosaminide 4-phosphates (AGPs) are potent ligands for the Toll-like receptor (TLR) 4. Using a murine (BALB/c) pneumonic plague model, we showed a single i.n. application of the vaccine provided 63% protection within 21 days against a Y. pestis CO92 100LD50 challenge. Protection reached 100% by 150 days. Using a homologous i.n. 1°/2° dose regimen, with the boost administered at varying times, 63% protection was achieved within 7 days and 100% protection was achieved by 21 days after the first immunization. Little or no protection was observed in animals that received antigens alone, and no protection was observed when the vaccine was administered to BALB/c TLR4 mutant mice. Vaccine-induced serum IgG titers to F1 and V-antigen were reflected in high titers for IgG1 and IgG2a, the latter reflecting a bias for a cell-mediated (TH1) immune response. This intranasal vaccine showed 90% protection in Sprague-Dawley rats challenged with 1000LD50. We conclude that lipid A mimetics are highly effective adjuvants for an i.n. plague vaccine. PMID:18722493

  19. Synergistic interaction of Smac mimetic and IFNα to trigger apoptosis in acute myeloid leukemia cells.

    PubMed

    Bake, Vanessa; Roesler, Stefanie; Eckhardt, Ines; Belz, Katharina; Fulda, Simone

    2014-12-28

    Therapeutic targeting of inhibitor of apoptosis (IAP) proteins by small-molecule inhibitors such as Smac mimetic is considered as a promising anticancer strategy to elicit apoptosis. Recent advances have renewed the interest in exploiting the antileukemic activity of interferon (IFN)α for the treatment of acute myeloid leukemia (AML). Here, we identify a novel synergistic interaction of the Smac mimetic BV6 and IFNα to trigger cell death in AML cells. Calculation of combination index (CI) confirms the synergism of BV6 and IFNα. In contrast to AML cells, no synergistic toxicity of BV6 and IFNα at equimolar concentrations is found against normal peripheral blood lymphocytes. BV6 and IFNα act in concert to stimulate expression of tumor necrosis factor (TNF)α and its secretion into the supernatant, thereby initiating an autocrine/paracrine TNFα/TNF receptor 1 (TNFR1) loop that drives cell death by BV6 and IFNα. Consistently, pharmacological inhibition of TNFα by the TNFα-blocking antibody Enbrel or genetic silencing of TNFR1 significantly reduces BV6/IFNα-induced cell death. In addition, BV6/IFNα-induced cell death depends on interferon regulatory factor (IRF)1, since RNA interference-imposed knockdown of IRF1 significantly rescues cell death. In conclusion, the identification of a novel synergistic antileukemic combination of Smac mimetic and IFNα has important implications for the development of innovative treatment strategies in AML. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Synergistic Effects of a Smac Mimetic with Doxorubicin Against Human Osteosarcoma.

    PubMed

    Kamata, Etsuko; Kawamoto, Teruya; Ueha, Takeshi; Hara, Hitomi; Fukase, Naomasa; Minoda, Masaya; Morishita, Masayuki; Takemori, Toshiyuki; Fujiwara, Shuichi; Nishida, Kotaro; Kuroda, Ryosuke; Kurosaka, Masahiro; Akisue, Toshihiro

    2017-11-01

    Second mitochondria-derived activator of caspase (Smac) is a proapoptogenic mitochondrial protein that antagonizes inhibitors of apoptosis proteins (IAPs), resulting in induction of apoptosis. In the present study we investigated the effects of a Smac mimetic in combination with doxorubicin against osteosarcoma. In vitro effects of the combination of a Smac mimetic AT-406 and doxorubicin on cell proliferation and apoptosis in osteosarcoma cell lines were examined using cell proliferation assays, flow cytometry, and immunoblot analyses. For in vivo experiments, human osteosarcoma xenografts were treated with combination of the two substances, and tumor volume and apoptotic activity in treated tumors were assessed. In vitro studies revealed that combination of the two substances significantly inhibited osteosarcoma proliferation with decreased cIAP1 expression and induced apoptosis in osteosarcoma cells. Combination of the two substances significantly suppressed osteosarcoma growth in vivo. Moreover, decreased cIAP1 expression and increased apoptotic activity were observed in tumors treated by their combination of the substances. The Smac mimetic AT-406 showed an apoptotic effect and a synergistic antitumor effect with doxorubicin on osteosarcoma. The combination of AT-406 and doxorubicin may serve as a novel therapeutic strategy for osteosarcoma treatment. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  1. A Potent Bivalent Smac Mimetic (SM-1200) Achieving Rapid, Complete and Durable Tumor Regression in Mice

    PubMed Central

    Sheng, Rong; Sun, Haiying; Liu, Liu; Lu, Jianfeng; McEachern, Donna; Wang, Guanfeng; Wen, Jianfeng; Min, Ping; Du, Zhenyun; Lu, Huirong; Kang, Sanmao; Guo, Ming; Yang, Dajun; Wang, Shaomeng

    2013-01-01

    We have designed, synthesized and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1 and cIAP2 with Ki values of 0.5 nM, 3.7 nM and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 nM and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development. PMID:23651223

  2. Vincristine resistance in relapsed neuroblastoma can be efficiently overcome by Smac mimetic LCL161 treatment.

    PubMed

    Frommann, Kristin; Appl, Birgit; Hundsdoerfer, Patrick; Reinshagen, Konrad; Eschenburg, Georg

    2018-01-31

    In spite of good initial therapy response neuroblastomas often spread to distant organs or relapse after periods of remission. Dysregulation of apoptosis, a hallmark of cancer, is often effected by elevated levels of antiapoptotic signals leading to resistance against chemotherapeutic drugs. Inhibitors of apoptosis proteins (IAPs) are crucial cellular apoptosis regulators. Targeting IAPs with Smac mimetics has been demonstrated as a promising strategy for treatment of neuroblastoma and other tumors. In paired neuroblastoma cell lines, obtained from the same patient at time of diagnosis (CHLA-15) and postchemotherapy during progressive disease (CHLA-20), expression of crucial IAPs was determined. Furthermore, effects of vincristine on viability, cytotoxicity, apoptosis induction and caspase-3/7 activation were determined. Cellular IAP-1 (cIAP-1) and X-linked IAP (XIAP) expression was increased in cell line CHLA-20. Moreover, biological effects of vincristine were significantly lower in these cells. Treatment of cells with Smac mimetic LCL161 increased the effects of vincristine in CHLA-15 cells and more importantly was able to overcome vincristine resistance in CHLA-20 cells. These findings demonstrate the potential of Smac mimetics for the development of novel therapeutic approaches for the treatment of relapsed/resistant neuroblastoma. Copyright © 2018. Published by Elsevier Inc.

  3. Inhibiting NANOG Enhances Efficacy of BH3 Mimetics | Center for Cancer Research

    Cancer.gov

    BCL-2 family proteins regulate cell fate. Some members promote cell survival while others induce programmed cell death. A third group, the BH3-only members, modulates the activities of the rest of the family. Some cancers, including those of the colon and rectum, express elevated levels of pro-survival BCL-2 members, which may protect cancer cells from chemotherapy. BH3 mimetics are novel therapies that target and inhibit these pro-survival family members. Two in particular, ABT-737 and ABT-199, have activity against multiple cancer types, though neither targets the protein MCL-1, which is related to the BCL-2 family and causes resistance to the BH3 mimetics. Recent studies have revealed that the embryonic regulator NANOG and the related gene NANOGP8 can indirectly regulate MCL-1 via the kinase AKT. Abid Mattoo, Ph.D., J. Milburn Jessup, M.D., and colleagues of CCR’s Laboratory of Experimental Carcinogenesis, hypothesized that combining NANOG or NANOGP8 inhibition with a BH3 mimetic would enhance the latter’s anticancer activity.

  4. Insulin mimetic effects of macrocyclic binuclear oxovanadium complexes on streptozotocin-induced experimental diabetes in rats.

    PubMed

    Ramachandran, B; Kandaswamy, M; Narayanan, V; Subramanian, S

    2003-11-01

    The vanadium complexes so far tested for their insulin mimetic effects are either mono- or binuclear and contain only acyclic ligands. The leaching or hydrolysis of vanadyl ions from these complexes is much easier, and hence they elicit side effects. In the present study, a new binuclear macrocyclic oxovanadium complex was synthesized, and its efficacy was studied on streptozotocin (STZ)-induced diabetic rats over a period of 30 days. The insulin mimetic effect of the complex was tested on the blood sugar level in the STZ-diabetic rats and on the activities of the carbohydrate-metabolizing enzymes present in the liver. Administration of vanadium complex to STZ-induced diabetic rats decreased blood glucose levels from hyperglycaemic to normoglycaemic when compared to diabetic rats. The activity of carbohydrate-metabolizing enzymes such as hexokinase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen content were increased to near normal in vanadium complex-administered diabetic rats. The biochemical studies such as assay of blood urea and glutamate oxaloacetate transaminases revealed that the complex is not toxic to the system. The nontoxic nature of this complex may be due to the presence of the vanadyl ions in an intact macrocyclic form. Further, the vanadyl ions present in the macrocyclic binuclear oxovanadium complex are very close to each other, and this may enhance the insulin mimetic activity by synergic effect.

  5. Superstretchable Nacre-Mimetic Graphene/Poly(vinyl alcohol) Composite Film Based on Interfacial Architectural Engineering.

    PubMed

    Zhao, Nifang; Yang, Miao; Zhao, Qian; Gao, Weiwei; Xie, Tao; Bai, Hao

    2017-05-23

    Through designing hierarchical structures, particularly optimizing the chemical and architectural interactions at its inorganic/organic interface, nacre has achieved an excellent combination of contradictory mechanical properties such as strength and toughness, which is highly demanded yet difficult to achieve by most synthetic materials. Most techniques applied to develop nacre-mimetic composites have been focused on mimicking the "brick-and-mortar" structure, but the interfacial architectural features, especially the asperities and mineral bridges of "bricks", have been rarely concerned, which are of equal importance for enhancing mechanical properties of nacre. Here, we used a modified bidirectional freezing method followed by uniaxial pressing and chemical reduction to assemble a nacre-mimetic graphene/poly(vinyl alcohol) composite film, with both asperities and bridges introduced in addition to the lamellar layers to mimic the interfacial architectural interactions found in nacre. As such, we have developed a composite film that is not only strong (up to ∼150.9 MPa), but also tough (up to ∼8.50 MJ/m 3 ), and highly stretchable (up to ∼10.44%), difficult to obtain by other methods. This was all achieved by only interfacial architectural engineering within the traditional "brick-and-mortar" structure, without introducing a third component or employing chemical cross-linker as in some other nacre-mimetic systems. More importantly, we believe that the design principles and processing strategies reported here can also be applied to other material systems to develop strong and stretchable materials.

  6. Geographic variation in mimetic precision among different species of coral snake mimics.

    PubMed

    Akcali, C K; Pfennig, D W

    2017-07-01

    Batesian mimicry is widespread, but whether and why different species of mimics vary geographically in resemblance to their model is unclear. We characterized geographic variation in mimetic precision among four Batesian mimics of coral snakes. Each mimic occurs where its model is abundant (i.e. in 'deep sympatry'), rare (i.e. at the sympatry/allopatry boundary or 'edge sympatry') and absent (i.e. in allopatry). Geographic variation in mimetic precision was qualitatively different among these mimics. In one mimic, the most precise individuals occurred in edge sympatry; in another, they occurred in deep sympatry; in the third, they occurred in allopatry; and in the fourth, precise mimics were not concentrated anywhere throughout their range. Mimicry was less precise in allopatry than in sympatry in only two mimics. We present several nonmutually exclusive hypotheses for these patterns. Generally, examining geographic variation in mimetic precision - within and among different mimics - offers novel insights into the causes and consequences of mimicry. © 2017 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2017 European Society For Evolutionary Biology.

  7. Role of phosphate on stability and catalase mimetic activity of cerium oxide nanoparticles.

    PubMed

    Singh, Ragini; Singh, Sanjay

    2015-08-01

    Cerium oxide nanoparticles (CeNPs) have been recently shown to scavenge reactive oxygen and nitrogen species (ROS and RNS) in different experimental model systems. CeNPs (3+) and CeNPs (4+) have been shown to exhibit superoxide dismutase (SOD) and catalase mimetic activity, respectively. Due to their nanoscale dimension, CeNPs are expected to interact with the components of biologically relevant buffers and medium, which could alter their catalytic properties. We have demonstrated earlier that CeNPs (3+) interact with phosphate and lose the SOD activity. However, very little is known about the interaction of CeNPs (4+) with the phosphate and other anions, predominantly present in biological buffers and their effects on the catalase mimetic-activity of these nanoparticles. In this study, we report that catalase mimetic-activity of CeNPs (4+) is resistant to the phosphate anions, pH changes and composition of cell culture media. Given the abundance of phosphate anions in the biological system, it is likely that internalized CeNPs would be influenced by cytoplasmic and nucleoplasmic concentration of phosphate. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Design, synthesis, and evaluation of an alpha-helix mimetic library targeting protein-protein interactions.

    PubMed

    Shaginian, Alex; Whitby, Landon R; Hong, Sukwon; Hwang, Inkyu; Farooqi, Bilal; Searcey, Mark; Chen, Jiandong; Vogt, Peter K; Boger, Dale L

    2009-04-22

    The design and solution-phase synthesis of an alpha-helix mimetic library as an integral component of a small-molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate alpha-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 x 20 x 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i + 4, i + 7 amino acid side chains of an alpha-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long-term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead alpha-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an alpha-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.

  9. Supramolecular assembly of multifunctional maspin-mimetic nanostructures as a potent peptide-based angiogenesis inhibitor

    DOE PAGES

    Zha, R. Helen; Sur, Shantanu; Boekhoven, Job; ...

    2014-11-08

    Aberrant angiogenesis plays a large role in pathologies ranging from tumor growth to macular degeneration. Anti-angiogenic proteins have thus come under scrutiny as versatile, potent therapeutics but face problems with purification and tissue retention. We report here on the synthesis of supramolecular nanostructures that mimic the anti-angiogenic activity of maspin, a class II tumor suppressor protein. These maspin-mimetic nanostructures are formed via self-assembly of small peptide amphiphiles containing the g-helix motif of maspin. Using tubulogenesis assays with human umbilical vein endothelial cells, we demonstrate that maspin-mimetic nanostructures show anti-angiogenic activity at concentrations that are significantly lower than those necessary formore » the g-helix peptide. Furthermore, in vivo assays in the chick chorioallantoic membrane show maspin-mimetic nanostructures to be effective over controls at inhibiting angiogenesis. Thus, in conclusion, the nanostructures investigated here offer an attractive alternative to the use of anti-angiogenic recombinant proteins in the treatment of cancer or other diseases involving abnormal blood vessel formation.« less

  10. Combining basal insulin analogs with glucagon-like peptide-1 mimetics.

    PubMed

    Perfetti, Riccardo

    2011-09-01

    Basal insulin analogs are recognized as an effective method of achieving and maintaining glycemic control for patients with type 2 diabetes. However, the progressive nature of the disease means that some individuals may require additional ways to maintain their glycemic goals. Intensification in these circumstances has traditionally been achieved by the addition of short-acting insulin to cover postprandial glucose excursions that are not targeted by basal insulin. However, intensive insulin regimens are associated with a higher risk of hypoglycemia and weight gain, which can contribute to a greater burden on patients. The combination of basal insulin with a glucagon-like peptide-1 (GLP-1) mimetic is a potentially attractive solution to this problem for some patients with type 2 diabetes. GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss. Although the combination has not been approved by regulatory authorities, preliminary evidence from mostly small-scale studies suggests that basal insulins in combination with GLP-1 mimetics do provide improvements in A1c and postprandial glucose with concomitant weight loss and no marked increase in the risk of hypoglycemia. These results are promising, but further studies are required, including comparisons with basal-bolus therapy, before the complex value of this association can be fully appreciated.

  11. Combining Basal Insulin Analogs with Glucagon-Like Peptide-1 Mimetics

    PubMed Central

    2011-01-01

    Abstract Basal insulin analogs are recognized as an effective method of achieving and maintaining glycemic control for patients with type 2 diabetes. However, the progressive nature of the disease means that some individuals may require additional ways to maintain their glycemic goals. Intensification in these circumstances has traditionally been achieved by the addition of short-acting insulin to cover postprandial glucose excursions that are not targeted by basal insulin. However, intensive insulin regimens are associated with a higher risk of hypoglycemia and weight gain, which can contribute to a greater burden on patients. The combination of basal insulin with a glucagon-like peptide-1 (GLP-1) mimetic is a potentially attractive solution to this problem for some patients with type 2 diabetes. GLP-1 mimetics target postprandial glucose and should complement the activity of basal insulins; they are also associated with a relatively low risk of associated hypoglycemia and moderate, but significant, weight loss. Although the combination has not been approved by regulatory authorities, preliminary evidence from mostly small-scale studies suggests that basal insulins in combination with GLP-1 mimetics do provide improvements in A1c and postprandial glucose with concomitant weight loss and no marked increase in the risk of hypoglycemia. These results are promising, but further studies are required, including comparisons with basal–bolus therapy, before the complex value of this association can be fully appreciated. PMID:21711120

  12. Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain barrier and impairs iron-dependent hippocampal neuron dendrite development.

    PubMed

    Bastian, T W; Duck, K A; Michalopoulos, G C; Chen, M J; Liu, Z-J; Connor, J R; Lanier, L M; Sola-Visner, M C; Georgieff, M K

    2017-03-01

    Essentials Potential neurodevelopmental side effects of thrombopoietin mimetics need to be considered. The effects of eltrombopag (ELT) on neuronal iron status and dendrite development were assessed. ELT crosses the blood-brain barrier and causes iron deficiency in developing neurons. ELT blunts dendrite maturation, indicating a need for more safety studies before neonatal use. Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g. eltrombopag [ELT]) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective To determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14 DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 μm ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 μm ELT, but not 2 μm ELT, decreased BdnfVI, Camk2a and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length were reduced in 6 μm ELT-treated neurons, resulting in blunted dendritic arbor complexity that

  13. Potent Bivalent Smac Mimetics: Effect of the Linker on Binding to Inhibitor of Apoptosis Proteins (IAPs) and Anticancer Activity

    PubMed Central

    Sun, Haiying; Liu, Liu; Lu, Jianfeng; Bai, Longchuan; Li, Xiaoqin; Nikolovska-Coleska, Zaneta; McEachern, Donna; Yang, Chao-Yie; Qiu, Su; Yi, Han; Sun, Duxin; Wang, Shaomeng

    2011-01-01

    We have synthesized and evaluated a series of non-peptidic, bivalent Smac mimetics as antagonists of the inhibitor of apoptosis proteins and new anticancer agents. All these bivalent Smac mimetics bind to full-length XIAP with low nanomolar affinities and function as ultra-potent antagonists of XIAP. While these Smac mimetics bind to cIAP1/2 with similar low nanomolar affinities, their potencies to induce degradation of cIAP1/2 proteins in cells differ by more than 100-fold. The most potent bivalent Smac mimetics inhibit cell growth with IC50 values from 1–3 nM in the MDA-MB-231 breast cancer cell line and are 100-times more potent than the least potent compounds. Determination of intracellular concentrations for several representative compounds showed that the linkers in these bivalent Smac mimetics significantly affect their intracellular concentrations, hence the overall cellular activity. Compound 27 completely inhibits tumor growth in the MDA-MB-231 xenografts, while causing no signs of toxicity in the animals. PMID:21462933

  14. Second mitochondria-derived activator of caspase (SMAC) mimetic potentiates tumor susceptibility toward natural killer cell-mediated killing.

    PubMed

    Brinkmann, Kerstin; Hombach, Andreas; Seeger, Jens Michael; Wagner-Stippich, Diana; Klubertz, Daniela; Krönke, Martin; Abken, Hinrich; Kashkar, Hamid

    2014-03-01

    Resistance to apoptosis is a hallmark of cancer, and represents an important mechanism of how tumor cells resist immune cell destruction. Mitochondria are the central regulators of the apoptotic machinery by releasing pro-apoptotic factors including cytochrome c and second mitochondria-derived activator of caspase (SMAC) upon mitochondrial outer membrane permeabilization (MOMP). Small molecules activating MOMP such as BH3 mimetics or antagonizers of the inhibitor of apoptosis proteins (IAPs) such as SMAC mimetics have recently engendered new optimism for a more individualized and effective cancer therapy. Here we show that a SMAC mimetic potentiates cancer cell killing by natural killer (NK) cells through reactivation of tumor cell apoptosis. Specifically, the SMAC mimetic enhances the susceptibility of tumor cells toward NK cell-mediated effector mechanisms involving death receptors and cytolytic granules containing perforin and granzymes by relieving caspase activity. Our data highlight for the first time the specific use of SMAC mimetics for boosting immune cell-mediated immunotherapy, representing a novel and promising approach in the treatment of cancer.

  15. Temporal dynamics of the mimetic allele frequency at the doublesex locus, which controls polymorphic Batesian mimicry in Papilio memnon butterflies.

    PubMed

    Komata, Shinya; Lin, Chung-Ping; Sota, Teiji

    2017-10-10

    Tracking allele frequencies is essential for understanding how polymorphisms of adaptive traits are maintained. In Papilio memnon butterflies, which exhibit a female-limited Batesian mimicry polymorphism (wing-pattern polymorphism), two alleles at the doublesex (dsx) locus correspond to mimetic and non-mimetic forms in females; males carry both dsx alleles but display only the non-mimetic form. This polymorphism is thought to be maintained by a negative frequency-dependent selection. By tracking dsx allele frequencies in both sexes at a Taiwanese site over four years, we found that the mimetic allele persists at intermediate frequencies even when the unpalatable model papilionid butterflies (Pachliopta and Atrophaneura species) were very rare or absent. The rates of male mate choice did not differ between the two female forms; neither did insemination number nor age composition, suggesting equivalent reproductive performance of the two forms over time. Our results characterised the temporal dynamics of the mimetic allele frequency in the field for the first time and give insights into underlying processes involved in the persistence of the female-limited Batesian mimicry polymorphism.

  16. Mimetic Relation as Matching-to-Sample Observing Response and the Emergence of Speaker Relations in Children with and without Hearing Impairments

    ERIC Educational Resources Information Center

    Elias, Nassim Chamel; Goyos, Celso

    2013-01-01

    This study investigated the effect of matching-to-sample and mimetic-relations teaching on the emergence of signed tact and textual repertoire through a multiple-baseline design, across three groups of three words in children with and without hearing impairments and with no reading repertoire. Following mimetic-relations teaching and the…

  17. Synthesis and screening of small-molecule α-helix mimetic libraries targeting protein-protein interactions.

    PubMed

    Moon, Heejo; Lim, Hyun-Suk

    2015-02-01

    α-Helices are the most common protein secondary structure and play a key role in mediating many protein-protein interactions (PPIs) by serving as recognition motifs. Given that aberrant α-helix-mediated PPIs are linked to various disease states, targeting such interactions with small-molecules represents an attractive strategy to develop therapeutic candidates for the related diseases. Over the last decade, significant efforts have been directed toward developing α-helix mimetic small-molecules that can modulate α-helix-mediated PPIs. In this review, we will highlight recent advances in the development of non-peptidic, small-molecule α-helix mimetics with a focus on library synthesis and screening methods to efficiently discover small-molecule α-helix mimetics. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Dietary restriction in pregnant rats causes gender-related hypertension and vascular dysfunction in offspring

    PubMed Central

    Ozaki, T; Nishina, H; Hanson, M A; Poston, L

    2001-01-01

    We have investigated the effects of moderate global undernutrition during gestation in the rat on the blood pressure of male and female offspring, and on the development of systemic vascular function. Pregnant Wistar rats were nutritionally restricted (R) by feeding with 70% of the normal gestation-matched dietary intake from 0 to 18 days gestation. R offspring were growth retarded at birth but of similar weight to controls (C) at 20 days. Systolic and/or diastolic and mean arterial blood pressures, measured directly by femoral artery catheter, were elevated from 60 days onward in male R offspring (mean arterial pressure: day 60, P < 0.01; day 100, P < 0.05; day 200, P < 0.005, R vs. C), and from 100 days onward in female R offspring (mean arterial pressure day 100 and day 200, P < 0.05; R vs. C). Maximal constriction to phenylephrine (PE) (P < 0.05) and to noradrenaline (NA) (P < 0.05) was reduced in isolated femoral arteries of day 20 R pups. These differences did not persist into adulthood. In male adult R offspring (200 days), maximal vasoconstriction to the thromboxane A2 mimetic, U46619 (P < 0.05) and sensitivity to potassium (P < 0.01) were enhanced. Moderate maternal undernutrition in rat gestation adversely affects cardiovascular function in the offspring. These abnormalities increase with age and are more pronounced in males. PMID:11136866

  19. Differential role of RIP1 in Smac mimetic-mediated chemosensitization of neuroblastoma cells.

    PubMed

    Czaplinski, Sebastian; Abhari, Behnaz Ahangarian; Torkov, Alica; Seggewiß, Dominik; Hugle, Manuela; Fulda, Simone

    2015-12-08

    We explored the potential of Smac mimetics, which antagonize Inhibitor of Apoptosis (IAP) proteins, for chemosensitization of neuroblastoma (NB). Here, we report that Smac mimetics, e.g. BV6, prime NB cells for chemotherapeutics including the topoisomerase II inhibitor doxorubicin (DOX) and vinca alkaloids such as Vincristine (VCR), Vinblastine (VBL) and Vinorelbine (VNR). Additionally, BV6 acts in concert with DOX or VCR to suppress long-term clonogenic growth. While BV6 causes rapid downregulation of cellular IAP (cIAP)1 protein and nuclear factor-kappaB (NF-κB) activation, DOX/BV6- or VCR/BV6-induced apoptosis occurs independently of NF-κB or TNFα signaling, since overexpression of dominant-negative IκBα superrepressor or the Tumor Necrosis Factor (TNF)α-blocking antibody Enbrel fail to block cell death. Mechanistic studies reveal that Receptor-interacting protein (RIP)1 is required for DOX/BV6-, but not for VCR/BV6-induced apoptosis, since transient or stable knockdown of RIP1 or the pharmacological RIP1 inhibitor necrostatin-1 significantly reduce apoptosis. By comparison, VCR/BV6-mediated apoptosis critically depends on the mitochondrial pathway. VCR/BV6 cotreatment causes phosphorylation of BCL-2 during mitotic arrest, enhanced activation of BAX and BAK and loss of mitochondrial membrane potential (MMP). Additionally, overexpression of BCL-2 profoundly suppresses VCR/BV6-induced apoptosis. Thus, BV6 sensitizes NB cells to chemotherapy-induced apoptosis via distinct initial signaling mechanisms depending on the chemotherapeutic drug. These findings provide novel mechanistic insights into Smac mimetic-mediated chemosensitization of NB.

  20. Mimetic Theory and the evolutionary paradox of schizophrenia: The archetypal scapegoat hypothesis.

    PubMed

    Riordan, Daniel Vincent

    2017-10-01

    Schizophrenia poses an evolutionary paradox, being genetically mediated yet associated with reduced fecundity. Numerous hypotheses have attempted to address this, but few describe how the schizophrenic phenotype itself might constitute an evolutionary adaptation. This paper draws on René Girard's theory on human origins, which claims that humans evolved a tendency to mimic both the desires and the behaviours of each other (mimetic theory). This would have promoted social cohesion and co-operation, but at the cost of intra-group rivalry and conflict. The mimetic dynamic would have escalated such conflicts into reciprocal internecine violence, threatening the survival of the entire group. Girard theorised that the "scapegoat mechanism" emerged, by which means such violence was curtailed by the unanimity of "all against one", thus allowing the mimetic impulse to safely evolve further, making language and complex social behaviours possible. Whereas scapegoating may have emerged in the entire population, and any member of a community could be scapegoated if necessary, this paper proposes that the scapegoat mechanism would have worked better in groups containing members who exhibited traits, recognised by all others, which singled them out as victims. Schizophrenia may be a functional adaptation, similar in evolutionary terms to altruism, in that it may have increased inclusive fitness, by providing scapegoat victims, the choice of whom was likely to be agreed upon unanimously, even during internecine conflict, thus restoring order and protecting the group from self-destruction. This evolutionary hypothesis, uses Girardian anthropology to combine the concept of the schizophrenic as religious shaman with that of the schizophrenic as scapegoat. It may help to reconcile divergent philosophical concepts of mental illness, and also help us to better understand, and thus counter, social exclusion and stigmatisation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  1. Characterization of Potent SMAC Mimetics that Sensitize Cancer Cells to TNF Family-Induced Apoptosis

    PubMed Central

    Welsh, Kate; Milutinovic, Snezana; Ardecky, Robert J.; Gonzalez-Lopez, Marcos; Ganji, Santhi Reddy; Finlay, Darren; Riedl, Stefan; Matsuzawa, Shu-ichi; Pinilla, Clemencia; Houghten, Richard; Vuori, Kristiina; Reed, John C.; Cosford, Nicholas D. P.

    2016-01-01

    Members of the Inhibitor of APoptosis (IAP) protein family suppress apoptosis within tumor cells, particularly in the context of immune cell-mediated killing by the tumor necrosis factor (TNF) superfamily cytokines. Most IAPs are opposed endogenously by the second mitochondrial activator of caspases (SMAC), which binds to selected baculovirus IAP repeat (BIR) domains of IAPs to displace interacting proteins. The development of SMAC mimetics as novel anticancer drugs has gained impetus, with several agents now in human clinical trials. To further understand the cellular mechanisms of SMAC mimetics, we focused on IAP family members cIAP1 and cIAP2, which are recruited to TNF receptor complexes where they support cell survival through NF-κB activation while suppressing apoptosis by preventing caspase activation. We established fluorescence polarization (FP) assays for the BIR2 and BIR3 domains of human cIAP1 and cIAP2 using fluorochrome-conjugated SMAC peptides as ligands. A library of SMAC mimetics was profiled using the FP assays to provide a unique structure activity relationship (SAR) analysis compared to previous assessments of binding to XIAP. Potent compounds displayed mean inhibitory binding constants (Ki) of 9 to 27 nM against the BIR3 domains of cIAP1 and cIAP2, respectively. Selected compounds were then characterized using cytotoxicity assays in which a cytokine-resistant human tumor cell line was sensitized to either TNF or lymphotoxin-α (LT-α). Cytotoxicity correlated closely with cIAP1 and cIAP2 BIR3 binding activity with the most potent compounds able to reduce cell viability by 50%. Further testing demonstrated that active compounds also inhibit RIP1 binding to BIR3 of cIAP1 and cIAP2 in vitro and reduce steady-state cIAP1 protein levels in cells. Altogether, these data inform the SAR for our SMAC mimetics with respect to cIAP1 and cIAP2, suggesting that these IAP family members play an important role in tumor cell resistance to cytotoxicity

  2. Characterization of Potent SMAC Mimetics that Sensitize Cancer Cells to TNF Family-Induced Apoptosis.

    PubMed

    Welsh, Kate; Milutinovic, Snezana; Ardecky, Robert J; Gonzalez-Lopez, Marcos; Ganji, Santhi Reddy; Teriete, Peter; Finlay, Darren; Riedl, Stefan; Matsuzawa, Shu-Ichi; Pinilla, Clemencia; Houghten, Richard; Vuori, Kristiina; Reed, John C; Cosford, Nicholas D P

    2016-01-01

    Members of the Inhibitor of APoptosis (IAP) protein family suppress apoptosis within tumor cells, particularly in the context of immune cell-mediated killing by the tumor necrosis factor (TNF) superfamily cytokines. Most IAPs are opposed endogenously by the second mitochondrial activator of caspases (SMAC), which binds to selected baculovirus IAP repeat (BIR) domains of IAPs to displace interacting proteins. The development of SMAC mimetics as novel anticancer drugs has gained impetus, with several agents now in human clinical trials. To further understand the cellular mechanisms of SMAC mimetics, we focused on IAP family members cIAP1 and cIAP2, which are recruited to TNF receptor complexes where they support cell survival through NF-κB activation while suppressing apoptosis by preventing caspase activation. We established fluorescence polarization (FP) assays for the BIR2 and BIR3 domains of human cIAP1 and cIAP2 using fluorochrome-conjugated SMAC peptides as ligands. A library of SMAC mimetics was profiled using the FP assays to provide a unique structure activity relationship (SAR) analysis compared to previous assessments of binding to XIAP. Potent compounds displayed mean inhibitory binding constants (Ki) of 9 to 27 nM against the BIR3 domains of cIAP1 and cIAP2, respectively. Selected compounds were then characterized using cytotoxicity assays in which a cytokine-resistant human tumor cell line was sensitized to either TNF or lymphotoxin-α (LT-α). Cytotoxicity correlated closely with cIAP1 and cIAP2 BIR3 binding activity with the most potent compounds able to reduce cell viability by 50%. Further testing demonstrated that active compounds also inhibit RIP1 binding to BIR3 of cIAP1 and cIAP2 in vitro and reduce steady-state cIAP1 protein levels in cells. Altogether, these data inform the SAR for our SMAC mimetics with respect to cIAP1 and cIAP2, suggesting that these IAP family members play an important role in tumor cell resistance to cytotoxicity

  3. Original nerve growth factor mimetic dipeptide GK-2 limits the manifestations of hemorrhagic stroke in rats.

    PubMed

    Kraineva, V A; Gudasheva, T A; Kotelnikova, S O; Antipova, T A; Seredenin, S B

    2013-03-01

    The protective effects of a new low-molecular-weight mimetic of nerve growth factor hexamethylene diamide bis-(N-monosuccinyl-L-glutamine-L-lysine; GK-2) were studied on the experimental model of hemorrhagic stroke (intracerebral posttraumatic hematoma) in rats. Intraperitoneal injections of GK-2 in a dose of 1 mg/kg 4 and 24 h after surgery and 24 h before testing the CNS function on days 3, 7, and 14 prevent death of experimental animals, reduce the neurological deficit, and normalized behavior.

  4. The Mimetic Finite Element Method and the Virtual Element Method for elliptic problems with arbitrary regularity.

    SciTech Connect

    Manzini, Gianmarco

    2012-07-13

    We develop and analyze a new family of virtual element methods on unstructured polygonal meshes for the diffusion problem in primal form, that use arbitrarily regular discrete spaces V{sub h} {contained_in} C{sup {alpha}} {element_of} N. The degrees of freedom are (a) solution and derivative values of various degree at suitable nodes and (b) solution moments inside polygons. The convergence of the method is proven theoretically and an optimal error estimate is derived. The connection with the Mimetic Finite Difference method is also discussed. Numerical experiments confirm the convergence rate that is expected from the theory.

  5. Self-assembly of bioactive peptides, peptide conjugates, and peptide mimetic materials.

    PubMed

    Edwards-Gayle, Charlotte J C; Hamley, Ian W

    2017-07-19

    Molecular self-assembly is a multi-disciplinary field of research, with potential chemical and biological applications. One of the main driving forces of self-assembly is molecular amphiphilicity, which can drive formation of complex and stable nanostructures. Self-assembling peptide and peptide conjugates have attracted great attention due to their biocompatibility, biodegradability and biofunctionality. Understanding assembly enables the better design of peptide amphiphiles which may form useful and functional nanostructures. This review covers self-assembly of amphiphilic peptides and peptide mimetic materials, as well as their potential applications.

  6. Molecular Design, Structures, and Activity of Antimicrobial Peptide-Mimetic Polymers

    PubMed Central

    Takahashi, Haruko; Palermo, Edmund F.; Yasuhara, Kazuma; Caputo, Gregory A.

    2014-01-01

    There is an urgent need for new antibiotics which are effective against drug-resistant bacteria without contributing to resistance development. We have designed and developed antimicrobial copolymers with cationic amphiphilic structures based on the mimicry of naturally occurring antimicrobial peptides. These copolymers exhibit potent antimicrobial activity against a broad spectrum of bacteria including methicillin-resistant Staphylococcus aureus with no adverse hemolytic activity. Notably, these polymers also did not result in any measurable resistance development in E. coli. The peptide-mimetic design principle offers significant flexibility and diversity in the creation of new antimicrobial materials and their potential biomedical applications. PMID:23832766

  7. Mimetic discretization of the Abelian Chern-Simons theory and link invariants

    SciTech Connect

    Di Bartolo, Cayetano; Grau, Javier; Leal, Lorenzo

    2013-12-15

    A mimetic discretization of the Abelian Chern-Simons theory is presented. The study relies on the formulation of a theory of differential forms in the lattice, including a consistent definition of the Hodge duality operation. Explicit expressions for the Gauss Linking Number in the lattice, which correspond to their continuum counterparts are given. A discussion of the discretization of metric structures in the space of transverse vector densities is presented. The study of these metrics could serve to obtain explicit formulae for knot an link invariants in the lattice.

  8. Arbitrary Order Mixed Mimetic Finite Differences Method with Nodal Degrees of Freedom

    SciTech Connect

    Iaroshenko, Oleksandr; Gyrya, Vitaliy; Manzini, Gianmarco

    2016-09-01

    In this work we consider a modification to an arbitrary order mixed mimetic finite difference method (MFD) for a diffusion equation on general polygonal meshes [1]. The modification is based on moving some degrees of freedom (DoF) for a flux variable from edges to vertices. We showed that for a non-degenerate element this transformation is locally equivalent, i.e. there is a one-to-one map between the new and the old DoF. Globally, on the other hand, this transformation leads to a reduction of the total number of degrees of freedom (by up to 40%) and additional continuity of the discrete flux.

  9. Peroxynitrite formed during a transient episode of brain ischaemia increases endothelium-derived hyperpolarization-type dilations in thromboxane/prostaglandin receptor-stimulated rat cerebral arteries.

    PubMed

    Onetti, Y; Dantas, A P; Pérez, B; McNeish, A J; Vila, E; Jiménez-Altayó, F

    2017-05-01

    Increased thromboxane A 2 and peroxynitrite are hallmarks of cerebral ischaemia/reperfusion (I/R). Stimulation of thromboxane/prostaglandin receptors (TP) attenuates endothelium-derived hyperpolarization (EDH). We investigated whether EDH-type middle cerebral artery (MCA) relaxations following TP stimulation are altered after I/R and the influence of peroxynitrite. Vascular function was determined by wire myography after TP stimulation with the thromboxane A 2 mimetic 9,11-dideoxy-9α, 11α -methano-epoxy prostaglandin F2α (U46619) in MCA of Sprague Dawley rats subjected to MCA occlusion (90 min)/reperfusion (24 h) or sham operation, and in non-operated (control) rats. Some rats were treated with saline or the peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron (III) (20 mg kg -1 ). Protein expression was evaluated in MCA and in human microvascular endothelial cells submitted to hypoxia (overnight)/reoxygenation (24 h) (H/R) using immunofluorescence and immunoblotting. In U46619-pre-constricted MCA, EDH-type relaxation by the proteinase-activated receptor 2 agonist serine-leucine-isoleucine-glycine-arginine-leucine-NH 2 (SLIGRL) was greater in I/R than sham rats due to an increased contribution of small-conductance calcium-activated potassium channels (SK C a ), which was confirmed by the enlarged relaxation to the SK C a activator N-cyclohexyl-N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine. I/R and H/R induced endothelial protein tyrosine nitration and filamentous-actin disruption. In control MCA, either cytochalasin D or peroxynitrite disrupted endothelial filamentous-actin and augmented EDH-type relaxation. Furthermore, peroxynitrite decomposition during I/R prevented the increase in EDH-type responses. Following TP stimulation in MCA, EDH-type relaxation to SLIGRL is greater after I/R due to endothelial filamentous-actin disruption by peroxynitrite, which prevents TP-induced block of SK C a input to EDH

  10. A conformational mimetic approach for the synthesis of carbocyclic nucleosides as anti-HCV leads.

    PubMed

    Kasula, Mohan; Balaraju, Tuniki; Toyama, Massaki; Thiyagarajan, Anandarajan; Bal, Chandralata; Baba, Masanori; Sharon, Ashoke

    2013-10-01

    Computer-aided approaches coupled with medicinal chemistry were used to explore novel carbocyclic nucleosides as potential anti-hepatitis C virus (HCV) agents. Conformational analyses were carried out on 6-amino-1H-pyrazolo[3,4-d]pyrimidine (6-APP)-based carbocyclic nucleoside analogues, which were considered as nucleoside mimetics to act as HCV RNA-dependent RNA polymerase (RdRp) inhibitors. Structural insight gained from the modeling studies revealed the molecular basis behind these nucleoside mimetics. The rationally chosen 6-APP analogues were prepared and evaluated for anti-HCV activity. RdRp SiteMap analysis revealed the presence of a hydrophobic cavity near C7 of the nucleosides; introduction of bulkier substituents at this position enhanced their activity. Herein we report the identification of an iodinated compound with an EC50 value of 6.6 μM as a preliminary anti-HCV lead. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. The action of mimetic peptides on connexins protects fibroblasts from the negative effects of ischemia reperfusion.

    PubMed

    Glass, Beverley J; Hu, Rebecca G; Phillips, Anthony R J; Becker, David L

    2015-10-15

    Connexins have been proposed as a target for therapeutic treatment of a variety of conditions. The main approaches have been by antisense or small peptides specific against connexins. Some of these peptides enhance communication while others interfere with connexin binding partners or bind to the intracellular and extracellular loops of connexins. Here, we explored the mechanism of action of a connexin mimetic peptide by evaluating its effect on gap junction channels, connexin protein levels and hemichannel activity in fibroblast cells under normal conditions and following ischemia reperfusion injury which elevates Cx43 levels, increases hemichannel activity and causes cell death. Our results showed that the effects of the mimetic peptide were concentration-dependent. High concentrations (100-300 μM) significantly reduced Cx43 protein levels and GJIC within 2 h, while these effects did not appear until 6 h when using lower concentrations (10-30 μM). Cell death can be reduced when hemichannel opening and GJIC were minimised. © 2015. Published by The Company of Biologists Ltd.

  12. Stick-slip friction of gecko-mimetic flaps on smooth and rough surfaces.

    PubMed

    Das, Saurabh; Cadirov, Nicholas; Chary, Sathya; Kaufman, Yair; Hogan, Jack; Turner, Kimberly L; Israelachvili, Jacob N

    2015-03-06

    The discovery and understanding of gecko 'frictional-adhesion' adhering and climbing mechanism has allowed researchers to mimic and create gecko-inspired adhesives. A few experimental and theoretical approaches have been taken to understand the effect of surface roughness on synthetic adhesive performance, and the implications of stick-slip friction during shearing. This work extends previous studies by using a modified surface forces apparatus to quantitatively measure and model frictional forces between arrays of polydimethylsiloxane gecko footpad-mimetic tilted microflaps against smooth and rough glass surfaces. Constant attachments and detachments occur between the surfaces during shearing, as described by an avalanche model. These detachments ultimately result in failure of the adhesion interface and have been characterized in this study. Stick-slip friction disappears with increasing velocity when the flaps are sheared against a smooth silica surface; however, stick-slip was always present at all velocities and loads tested when shearing the flaps against rough glass surfaces. These results demonstrate the significance of pre-load, shearing velocity, shearing distances, commensurability and shearing direction of gecko-mimetic adhesives and provide us a simple model for analysing and/or designing such systems. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  13. Stick–slip friction of gecko-mimetic flaps on smooth and rough surfaces

    PubMed Central

    Das, Saurabh; Cadirov, Nicholas; Chary, Sathya; Kaufman, Yair; Hogan, Jack; Turner, Kimberly L.; Israelachvili, Jacob N.

    2015-01-01

    The discovery and understanding of gecko ‘frictional-adhesion’ adhering and climbing mechanism has allowed researchers to mimic and create gecko-inspired adhesives. A few experimental and theoretical approaches have been taken to understand the effect of surface roughness on synthetic adhesive performance, and the implications of stick–slip friction during shearing. This work extends previous studies by using a modified surface forces apparatus to quantitatively measure and model frictional forces between arrays of polydimethylsiloxane gecko footpad-mimetic tilted microflaps against smooth and rough glass surfaces. Constant attachments and detachments occur between the surfaces during shearing, as described by an avalanche model. These detachments ultimately result in failure of the adhesion interface and have been characterized in this study. Stick–slip friction disappears with increasing velocity when the flaps are sheared against a smooth silica surface; however, stick–slip was always present at all velocities and loads tested when shearing the flaps against rough glass surfaces. These results demonstrate the significance of pre-load, shearing velocity, shearing distances, commensurability and shearing direction of gecko-mimetic adhesives and provide us a simple model for analysing and/or designing such systems. PMID:25589569

  14. Glycosides from Stevia rebaudiana Bertoni Possess Insulin-Mimetic and Antioxidant Activities in Rat Cardiac Fibroblasts

    PubMed Central

    Prata, Cecilia; Zambonin, Laura; Rizzo, Benedetta; Vieceli Dalla Sega, Francesco

    2017-01-01

    Stevia rebaudiana Bertoni is a shrub having a high content of sweet diterpenoid glycosides in its leaves, mainly stevioside and rebaudioside A, which are used as noncaloric, natural sweeteners. The aim of this study was to deepen the knowledge about the insulin-mimetic effect exerted by four different mixtures of steviol glycosides, rich in stevioside and rebaudioside A, in neonatal rat cardiac fibroblasts. The potential antioxidant activity of these steviol glycosides was also assessed, as oxidative stress is associated with diabetes. Likewise the insulin effect, steviol glycosides caused an increase in glucose uptake into rat fibroblasts by activating the PI3K/Akt pathway, thus inducing Glut4 translocation to the plasma membrane. The presence of S961, an insulin antagonist, completely abolished these effects, allowing to hypothesize that steviol glycosides could act as ligands of the same receptor engaged by insulin. Moreover, steviol glycosides counteracted oxidative stress by increasing reduced glutathione intracellular levels and upregulating expression and activity of the two antioxidant enzymes superoxide dismutase and catalase. The present work unravels the insulin-mimetic effect and the antioxidant property exerted by steviol glycosides, suggesting their potential beneficial role in the cotreatment of diabetes and in health maintenance. PMID:28947927

  15. Bioinspired exosome-mimetic nanovesicles for targeted delivery of chemotherapeutics to malignant tumors.

    PubMed

    Jang, Su Chul; Kim, Oh Youn; Yoon, Chang Min; Choi, Dong-Sic; Roh, Tae-Young; Park, Jaesung; Nilsson, Jonas; Lötvall, Jan; Kim, Yoon-Keun; Gho, Yong Song

    2013-09-24

    Exosomes, the endogenous nanocarriers that can deliver biological information between cells, were recently introduced as new kind of drug delivery system. However, mammalian cells release relatively low quantities of exosomes, and purification of exosomes is difficult. Here, we developed bioinspired exosome-mimetic nanovesicles that deliver chemotherapeutics to the tumor tissue after systemic administration. The chemotherapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes (10, 5, and 1 μm). These cell-derived nanovesicles have similar characteristics with the exosomes but have 100-fold higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. In vitro, chemotherapeutic drug-loaded nanovesicles induced TNF-α-stimulated endothelial cell death in a dose-dependent manner. In vivo, experiments in mice showed that the chemotherapeutic drug-loaded nanovesicles traffic to tumor tissue and reduce tumor growth without the adverse effects observed with equipotent free drug. Furthermore, compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo antitumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. Importantly, removal of the plasma membrane proteins by trypsinization eliminated the therapeutic effects of the nanovesicles both in vitro and in vivo. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to effectively deliver chemotherapeutics to treat malignant tumors.

  16. RNAi delivery by exosome-mimetic nanovesicles - Implications for targeting c-Myc in cancer.

    PubMed

    Lunavat, Taral R; Jang, Su Chul; Nilsson, Lisa; Park, Hyun Taek; Repiska, Gabriela; Lässer, Cecilia; Nilsson, Jonas A; Gho, Yong Song; Lötvall, Jan

    2016-09-01

    To develop RNA-based therapeutics, it is crucial to create delivery vectors that transport the RNA molecule into the cell cytoplasm. Naturally released exosomes vesicles (also called "Extracellular Vesicles") have been proposed as possible RNAi carriers, but their yield is relatively small in any cell culture system. We have previously generated exosome-mimetic nanovesicles (NV) by serial extrusions of cells through nano-sized filters, which results in 100-times higher yield of extracellular vesicles. We here test 1) whether NV can be loaded with siRNA exogenously and endogenously, 2) whether the siRNA-loaded NV are taken up by recipient cells, and 3) whether the siRNA can induce functional knock-down responses in recipient cells. A siRNA against GFP was first loaded into NV by electroporation, or a c-Myc shRNA was expressed inside of the cells. The NV were efficiently loaded with siRNA with both techniques, were taken up by recipient cells, which resulted in attenuation of target gene expression. In conclusion, our study suggests that exosome-mimetic nanovesicles can be a platform for RNAi delivery to cell cytoplasm. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Evidence for a Müllerian mimetic radiation in Asian pitvipers

    PubMed Central

    Sanders, K.L; Malhotra, A; Thorpe, R.S

    2006-01-01

    Müllerian mimicry, in which toxic species gain mutual protection from shared warning signals, is poorly understood in vertebrates, reflecting a paucity of examples. Indirect evidence for mimicry is found if monophyletic species or clades show parallel geographic variation in warning patterns. Here, we evaluate a hypothesis of Müllerian mimicry for the pitvipers in Southeast Asia using a phylogeny derived from DNA sequences from four combined mitochondrial regions. Mantel matrix correlation tests show that conspicuous red colour pattern elements are significantly associated with sympatric and parapatric populations in four genera. To our knowledge, this represents the first evidence of a Müllerian mimetic radiation in vipers. The putative mimetic patterns are rarely found in females. This appears paradoxical in light of the Müllerian prediction of monomorphism, but may be explained by divergent selection pressures on the sexes, which have different behaviours. We suggest that biased predation on active males causes selection for protective warning coloration, whereas crypsis is favoured in relatively sedentary females. PMID:16600892

  18. Evidence for a Müllerian mimetic radiation in Asian pitvipers.

    PubMed

    Sanders, K L; Malhotra, A; Thorpe, R S

    2006-05-07

    Müllerian mimicry, in which toxic species gain mutual protection from shared warning signals, is poorly understood in vertebrates, reflecting a paucity of examples. Indirect evidence for mimicry is found if monophyletic species or clades show parallel geographic variation in warning patterns. Here, we evaluate a hypothesis of Müllerian mimicry for the pitvipers in Southeast Asia using a phylogeny derived from DNA sequences from four combined mitochondrial regions. Mantel matrix correlation tests show that conspicuous red colour pattern elements are significantly associated with sympatric and parapatric populations in four genera. To our knowledge, this represents the first evidence of a Müllerian mimetic radiation in vipers. The putative mimetic patterns are rarely found in females. This appears paradoxical in light of the Müllerian prediction of monomorphism, but may be explained by divergent selection pressures on the sexes, which have different behaviours. We suggest that biased predation on active males causes selection for protective warning coloration, whereas crypsis is favoured in relatively sedentary females.

  19. Eltrombopag, a thrombopoietin mimetic, crosses the blood-brain-barrier and impairs iron-dependent hippocampal neuron dendrite development

    PubMed Central

    Bastian, Thomas W.; Duck, Kari A.; Michalopoulos, George C.; Chen, Michael J.; Liu, Zhi-Jian; Connor, James R.; Lanier, Lorene M.; Sola-Visner, Martha C.; Georgieff, Michael K.

    2017-01-01

    Background Thrombocytopenia is common in sick neonates. Thrombopoietin mimetics (e.g., eltrombopag (ELT)) might provide an alternative therapy for selected neonates with severe and prolonged thrombocytopenia, and for infants and young children with different varieties of thrombocytopenia. However, ELT chelates intracellular iron, which may adversely affect developing organs with high metabolic requirements. Iron deficiency (ID) is particularly deleterious during brain development, impairing neuronal myelination, dopamine signaling, and dendritic maturation and ultimately impairing long-term neurological function (e.g. hippocampal-dependent learning and memory). Objective Determine whether ELT crosses the blood-brain barrier (BBB), causes neuronal ID and impairs hippocampal neuron dendrite maturation. Methods ELT transport across the BBB was assessed using primary bovine brain microvascular endothelial cells. Embryonic mouse primary hippocampal neuron cultures were treated with ELT or deferoxamine (DFO, an iron chelator) from 7 days in vitro (DIV) through 14DIV and assessed for gene expression and neuronal dendrite complexity. Results ELT crossed the BBB in a time-dependent manner. 2 and 6 μM ELT increased Tfr1 and Slc11a2 (iron-responsive genes involved in neuronal iron uptake) mRNA levels, indicating neuronal ID. 6 μM ELT, but not 2 μM ELT, decreased BdnfVI, Camk2a, and Vamp1 mRNA levels, suggesting impaired neuronal development and synaptic function. Dendrite branch number and length was reduced in 6 μM ELT-treated neurons, resulting in blunted dendritic arbor complexity that was similar to DFO-treated neurons. Conclusions ELT treatment during development may impair neuronal structure due to neuronal ID. Pre-clinical in vivo studies are warranted to assess ELT safety during periods of rapid brain development. PMID:28005311

  20. A Peptide Mimetic Targeting Trans-Homophilic NCAM Binding Sites Promotes Spatial Learning and Neural Plasticity in the Hippocampus

    PubMed Central

    Kohler, Lene B.; Fantin, Martina; Jennings, Alistair; Venero, Cesar; Popov, Victor; Rusakov, Dmitri; Stewart, Michael G.; Bock, Elisabeth; Berezin, Vladimir; Sandi, Carmen

    2011-01-01

    The key roles played by the neural cell adhesion molecule (NCAM) in plasticity and cognition underscore this membrane protein as a relevant target to develop cognitive-enhancing drugs. However, NCAM is a structurally and functionally complex molecule with multiple domains engaged in a variety of actions, which raise the question as to which NCAM fragment should be targeted. Synthetic NCAM mimetic peptides that mimic NCAM sequences relevant to specific interactions allow identification of the most promising targets within NCAM. Recently, a decapeptide ligand of NCAM—plannexin, which mimics a homophilic trans-binding site in Ig2 and binds to Ig3—was developed as a tool for studying NCAM's trans-interactions. In this study, we investigated plannexin's ability to affect neural plasticity and memory formation. We found that plannexin facilitates neurite outgrowth in primary hippocampal neuronal cultures and improves spatial learning in rats, both under basal conditions and under conditions involving a deficit in a key plasticity-promoting posttranslational modification of NCAM, its polysialylation. We also found that plannexin enhances excitatory synaptic transmission in hippocampal area CA1, where it also increases the number of mushroom spines and the synaptic expression of the AMPAR subunits GluA1 and GluA2. Altogether, these findings provide compelling evidence that plannexin is an important facilitator of synaptic functional, structural and molecular plasticity in the hippocampal CA1 region, highlighting the fragment in NCAM's Ig3 module where plannexin binds as a novel target for the development of cognition-enhancing drugs. PMID:21887252

  1. Intrinsic and chemo-sensitizing activity of SMAC-mimetics on high-risk childhood acute lymphoblastic leukemia.

    PubMed

    Schirmer, M; Trentin, L; Queudeville, M; Seyfried, F; Demir, S; Tausch, E; Stilgenbauer, S; Eckhoff, S M; Meyer, L H; Debatin, K-M

    2016-01-14

    SMAC-mimetics represent a targeted therapy approach to overcome apoptosis resistance in many tumors. Here, we investigated the efficacy of the SMAC-mimetic BV6 in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In ALL cell lines, intrinsic apoptosis sensitivity was associated with rapid cIAP degradation, NF-κB activation, TNF-α secretion and induction of an autocrine TNF-α-dependent cell death loop. This pattern of responsiveness was also observed upon ex vivo analysis of 40 primograft BCP-ALL samples. Treatment with BV6 induced cell death in the majority of ALL primografts including leukemias with high-risk and poor-prognosis features. Inhibition of cell death by the TNF receptor fusion protein etanercept demonstrated that BV6 activity is dependent on TNF-α. In a preclinical NOD/SCID/huALL model of high-risk ALL, marked anti-leukemia effectivity and significantly prolonged survival were observed upon BV6 treatment. Interestingly, also in vivo, intrinsic SMAC-mimetic activity was mediated by TNF-α. Importantly, BV6 increased the effectivity of conventional induction therapy including vincristine, dexamethasone and asparaginase leading to prolonged remission induction. These data suggest SMAC-mimetics as an important addendum to efficient therapy of pediatric BCP-ALL.

  2. The spread of adenoviral vectors to central nervous system through pathway of cochlea in mimetic aging and young rats.

    PubMed

    Chen, X; Zhao, X; Hu, Y; Lan, F; Sun, H; Fan, G; Sun, Y; Wu, J; Kong, W; Kong, W

    2015-11-01

    There is no definitive conclusion concerning the spread of viral vectors to the brain after a cochlear inoculation. In addition, some studies have reported different distribution profiles of viral vectors in the central auditory system after a cochlear inoculation. Thus, rats were grouped into either a mimetic aging group or a young group and transfected with adenoviral vectors (AdVs) by round window membrane injection. The distribution of AdV in central nervous system (CNS) was demonstrated in the two groups with transmission electron microscopy and immunofluorescence. We found that the AdV could disseminate into the CNS and that the neuronal damage and stress-induced GRP78 expression were reduced after transfection with PGC-1α, as compared with the control vectors, especially in the mimetic aging group. We also found that the host immune response was degraded in CNS in the mimetic aging group after transduction through the cochlea, as compared with the young group. These results demonstrate that viral vectors can disseminate into the CNS through the cochlea. Moreover, mimetic aging induced by D-galactose could facilitate the spread of viral vectors into the CNS from the cochlea. These findings may indicate a new potential approach for gene therapy against age-related diseases in the CNS.

  3. L-Eye to Me: The Combined Role of Need for Cognition and Facial Trustworthiness in Mimetic Desires

    ERIC Educational Resources Information Center

    Treinen, Evelyne; Corneille, Olivier; Luypaert, Gaylord

    2012-01-01

    Recent studies showed that stimuli are evaluated more favourably when they are perceived to capture others' attention, an effect coined "mimetic desire". The aim of the present research was to examine the combined role of Need for Cognition and target's facial trustworthiness in this effect. Participants saw movie excerpts of trustworthy and…

  4. Apolipoprotein A-I Mimetic Peptides: Discordance Between In Vitro and In Vivo Properties-Brief Report.

    PubMed

    Ditiatkovski, Michael; Palsson, Jonatan; Chin-Dusting, Jaye; Remaley, Alan T; Sviridov, Dmitri

    2017-07-01

    Apolipoprotein A-I (apoA-I) mimetic peptides have antiatherogenic properties of high-density lipoprotein in vitro and have been shown to inhibit atherosclerosis in vivo. It is unclear, however, if each in vitro antiatherogenic property of these peptides translates to a corresponding activity in vivo, and if so, which of these contributes most to reduce atherosclerosis. The effect of 7 apoA-I mimetic peptides, which were developed to selectively reproduce a specific component of the antiatherogenic properties of apoA-I, on the development of atherosclerosis was investigated in apolipoprotein E-deficient mice fed a high-fat diet for 4 or 12 weeks. The peptides include those that selectively upregulate cholesterol efflux, or are anti-inflammatory, or have antioxidation properties. All the peptides studied effectively inhibited the in vivo development of atherosclerosis in this model to the same extent. However, none of the peptides had the same selective effect in vivo as they had exhibited in vitro. None of the tested peptides affected plasma lipoprotein profile; capacity of plasma to support cholesterol efflux was increased modestly and similarly for all peptides. There is a discordance between the selective in vitro and in vivo functional properties of apoA-I mimetic peptides, and the in vivo antiatherosclerotic effect of apoA-I-mimetic peptides is independent of their in vitro functional profile. Comparing the properties of apoA-I mimetic peptides in plasma rather than in the lipid-free state is better for predicting their in vivo effects on atherosclerosis. © 2017 American Heart Association, Inc.

  5. RSL3 and Erastin differentially regulate redox signaling to promote Smac mimetic-induced cell death.

    PubMed

    Dächert, Jasmin; Schoeneberger, Hannah; Rohde, Katharina; Fulda, Simone

    2016-09-27

    Redox mechanisms play an important role in the control of various signaling pathways. Here, we report that Second mitochondrial activator of caspases (Smac) mimetic-induced cell death is regulated by redox signaling. We show that RSL3, a glutathione (GSH) peroxidase (GPX) 4 inhibitor, or Erastin, an inhibitor of the cystine/glutamate antiporter, cooperate with the Smac mimetic BV6 to induce reactive oxygen species (ROS)-dependent cell death in acute lymphoblastic leukemia (ALL) cells. Addition of the caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) fails to rescue ROS-induced cell death, demonstrating that RSL3/BV6- or Erastin/BV6-induced cell death occurs in a caspase-independent manner. Interestingly, the iron chelator Deferoxamine (DFO) significantly inhibits RSL3/BV6-induced cell death, whereas it is unable to rescue cell death by Erastin/BV6, showing that RSL3/BV6-, but not Erastin/BV6-mediated cell death depends on iron. ROS production is required for both RSL3/BV6- and Erastin/BV6-induced cell death, since the ROS scavenger α-tocopherol (α-Toc) rescues RSL3/BV6- and Erastin/BV6-induced cell death. By comparison, genetic or pharmacological inhibition of lipid peroxidation by GPX4 overexpression or ferrostatin (Fer)-1 significantly decreases RSL3/BV6-, but not Erastin/BV6-induced cell death, despite inhibition of lipid peroxidation upon exposure to RSL3/BV6 or Erastin/BV6. Of note, inhibition of lipid peroxidation by Fer-1 protects from RSL3/BV6-, but not from Erastin/BV6-stimulated ROS production, indicating that other forms of ROS besides lipophilic ROS occur during Erastin/BV6-induced cell death. Taken together, RSL3/BV6 and Erastin/BV6 differentially regulate redox signaling and cell death in ALL cells. While RSL3/BV6 cotreatment induces ferroptotic cell death, Erastin/BV6 stimulates oxidative cell death independently of iron. These findings have important implications for the therapeutic targeting of redox signaling to

  6. Activation and Inactivation of Primary Human Immunodeficiency Virus Envelope Glycoprotein Trimers by CD4-Mimetic Compounds

    PubMed Central

    Madani, Navid; Princiotto, Amy M.; Zhao, Connie; Jahanbakhshsefidi, Fatemeh; Mertens, Max; Herschhorn, Alon; Melillo, Bruno; Smith, Amos B.

    2016-01-01

    ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry into cells is mediated by the viral envelope glycoproteins (Env), a trimer of three gp120 exterior glycoproteins, and three gp41 transmembrane glycoproteins. The metastable Env is triggered to undergo entry-related conformational changes when gp120 binds sequentially to the receptors, CD4 and CCR5, on the target cell. Small-molecule CD4-mimetic compounds (CD4mc) bind gp120 and act as competitive inhibitors of gp120-CD4 engagement. Some CD4mc have been shown to trigger Env prematurely, initially activating Env function, followed by rapid and irreversible inactivation. Here, we study CD4mc with a wide range of anti-HIV-1 potencies and demonstrate that all tested CD4mc are capable of activating as well as inactivating Env function. Biphasic dose-response curves indicated that the occupancy of the protomers in the Env trimer governs viral activation versus inactivation. One CD4mc bound per Env trimer activated HIV-1 infection. Envs with two CD4mc bound were activated for infection of CD4-negative, CCR5-positive cells, but the infection of CD4-positive, CCR5-positive cells was inhibited. Virus was inactivated when all three Env protomers were occupied by the CD4mc, and gp120 shedding from the Env trimer was increased in the presence of some CD4mc. Env reactivity and the on rates of CD4mc binding to the Env trimer were found to be important determinants of the potency of activation and entry inhibition. Cross-sensitization of Env protomers that do not bind the CD4mc to neutralization by an anti-V3 antibody was not evident. These insights into the mechanism of antiviral activity of CD4mc should assist efforts to optimize their potency and utility. IMPORTANCE The trimeric envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) mediate virus entry into host cells. Binding to the host cell receptors, CD4 and CCR5, triggers changes in the conformation of the HIV-1 envelope glycoprotein trimer important

  7. A comparative investigation of mussel-mimetic sealants for fetal membrane repair.

    PubMed

    Perrini, Michela; Barrett, Devin; Ochsenbein-Koelble, Nicole; Zimmermann, Roland; Messersmith, Phillip; Ehrbar, Martin

    2016-05-01

    Towards the prevention of iatrogenic preterm premature rupture of the fetal membrane, two mussel-mimetic tissue adhesives (cT and cPEG) have been compared and qualified as possible sealants for membrane repair. Monotonic and cyclic inflation tests of repaired fetal membranes were carried out in order to investigate the performance of the glues under quasi-static, fast, and repeated loading. Finite element simulations of repaired and inflated synthetic membranes allowed to compare cT and cPEG under large deformations. Both adhesives seal the membrane well, resisting pressures higher than the intra-uterine baseline. Only under repeated mechanical load, as well as under fast and acute deformation of the membrane, the sealing performance has deteriorated. Even though cT loses adhesion to the deformed membrane, it is able to withstand high deformations and pressures without rupturing, while cPEG breaks. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. The mimetic finite difference method for the Landau–Lifshitz equation

    DOE PAGES

    Kim, Eugenia Hail; Lipnikov, Konstantin Nikolayevich

    2017-01-01

    The Landau–Lifshitz equation describes the dynamics of the magnetization inside ferromagnetic materials. This equation is highly nonlinear and has a non-convex constraint (the magnitude of the magnetization is constant) which poses interesting challenges in developing numerical methods. We develop and analyze explicit and implicit mimetic finite difference schemes for this equation. These schemes work on general polytopal meshes which provide enormous flexibility to model magnetic devices with various shapes. A projection on the unit sphere is used to preserve the magnitude of the magnetization. We also provide a proof that shows the exchange energy is decreasing in certain conditions. Themore » developed schemes are tested on general meshes that include distorted and randomized meshes. As a result, the numerical experiments include a test proposed by the National Institute of Standard and Technology and a test showing formation of domain wall structures in a thin film.« less

  9. Design and synthesis of type-III mimetics of ω-conotoxin GVIA

    NASA Astrophysics Data System (ADS)

    Baell, Jonathan B.; Forsyth, Stewart A.; Gable, Robert W.; Norton, Raymond S.; Mulder, Roger J.

    2001-12-01

    Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. Our approach involves interactive design of conformationally defined molecular scaffolds that project certain functional groups in a way that mimics the projection of important binding residues as determined in the parent structure. These design principles are discussed and applied to the structurally defined polypeptide, ω-conotoxin GVIA, which blocks voltage-gated, neuronal N-type calcium channels. These ion channels represent therapeutic targets for the development of new analgesics that can treat chronic pain. It is shown how a discontinuous, 3-residue pharmacophore of GVIA can be mimicked by different molecular scaffolds. It is illustrated how such 1st generation leads must necessarily be weak and that optimisability must therefore be built-in during the design process.

  10. Synthesis of a polymerizable, bivalent glycan mimetic of the HIV envelope spike gp120.

    PubMed

    Sletten, Eric T; Svec, Riley L; Nguyen, Hien M

    2015-06-03

    A synthetic study on the creation of a bivalent, ROMP capable monomer has the ability to be polymerized into the corresponding neo-glycopolymer mimetic of the surface glycans on gp120 envelope spike of the HIV virus. In our approach, we have developed a new strategy for orthogonally attaching both the terminal Manα1-2Man disaccharide unit of the D1 arm of Man9GlcNAc2 of HIV gp120 and the terminal Manα1-2 unit of its D2 arm to a bivalent scaffold to produce the corresponding polymerizable monomer. The Manα1-2 saccharide moieties were assembled using a nickel catalyst, Ni(4-F-PhCN) 4 (OTf) 2 , to activate trihaloacetimidate donors under mild and operationally simple procedure.

  11. Synthesis of a polymerizable, bivalent glycan mimetic of the HIV envelope spike gp120

    PubMed Central

    Sletten, Eric T.; Svec, Riley L.; Nguyen, Hien M.

    2015-01-01

    A synthetic study on the creation of a bivalent, ROMP capable monomer has the ability to be polymerized into the corresponding neo-glycopolymer mimetic of the surface glycans on gp120 envelope spike of the HIV virus. In our approach, we have developed a new strategy for orthogonally attaching both the terminal Manα1-2Man disaccharide unit of the D1 arm of Man9GlcNAc2 of HIV gp120 and the terminal Manα1-2 unit of its D2 arm to a bivalent scaffold to produce the corresponding polymerizable monomer. The Manα1-2 saccharide moieties were assembled using a nickel catalyst, Ni(4-F-PhCN)4(OTf)2, to activate trihaloacetimidate donors under mild and operationally simple procedure. PMID:26019370

  12. Collagen mimetic peptide engineered M13 bacteriophage for collagen targeting and imaging in cancer.

    PubMed

    Jin, Hyo-Eon; Farr, Rebecca; Lee, Seung-Wuk

    2014-11-01

    Collagens are over-expressed in various human cancers and subsequently degraded and denatured by proteolytic enzymes, thus making them a target for diagnostics and therapeutics. Genetically engineered bacteriophage (phage) is a promising candidate for the development of imaging or therapeutic materials for cancer collagen targeting due to its promising structural features. We genetically engineered M13 phages with two functional peptides, collagen mimetic peptide and streptavidin binding peptide, on their minor and major coat proteins, respectively. The resulting engineered phage functions as a therapeutic or imaging material to target degraded and denatured collagens in cancerous tissues. We demonstrated that the engineered phages are able to target and label abnormal collagens expressed on A549 human lung adenocarcinoma cells after the conjugation with streptavidin-linked fluorescent agents. Our engineered collagen binding phage could be a useful platform for abnormal collagen imaging and drug delivery in various collagen-related diseases. Published by Elsevier Ltd.

  13. Advances in the design and higher-order assembly of collagen mimetic peptides for regenerative medicine.

    PubMed

    Strauss, Kevin; Chmielewski, Jean

    2017-08-01

    Regenerative medicine makes use of cell-supporting biomaterials to replace lost or damaged tissue. Collagen holds great potential in this regard caused by its biocompatibility and structural versatility. While natural collagen has shown promise for regenerative medicine, collagen mimetic peptides (CMPs) have emerged that allow far higher degrees of customization and ease of preparation. A wide range of two and three-dimensional assemblies have been generated from CMPs, many of which accommodate cellular adhesion and encapsulation, through careful sequence design and the exploitation of electrostatic and hydrophobic forces. But the methodology that has generated the greatest plethora of viable biomaterials is metal-promoted assembly of CMP triple helices-a rapid process that occurs under physiological conditions. Architectures generated in this manner promote cell growth, enable directed attachment of bioactive cargo, and produce living tissue. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. β-cell-mimetic designer cells provide closed-loop glycemic control.

    PubMed

    Xie, Mingqi; Ye, Haifeng; Wang, Hui; Charpin-El Hamri, Ghislaine; Lormeau, Claude; Saxena, Pratik; Stelling, Jörg; Fussenegger, Martin

    2016-12-09

    Chronically deregulated blood-glucose concentrations in diabetes mellitus result from a loss of pancreatic insulin-producing β cells (type 1 diabetes, T1D) or from impaired insulin sensitivity of body cells and glucose-stimulated insulin release (type 2 diabetes, T2D). Here, we show that therapeutically applicable β-cell-mimetic designer cells can be established by minimal engineering of human cells. We achieved glucose responsiveness by a synthetic circuit that couples glycolysis-mediated calcium entry to an excitation-transcription system controlling therapeutic transgene expression. Implanted circuit-carrying cells corrected insulin deficiency and self-sufficiently abolished persistent hyperglycemia in T1D mice. Similarly, glucose-inducible glucagon-like peptide 1 transcription improved endogenous glucose-stimulated insulin release and glucose tolerance in T2D mice. These systems may enable a combination of diagnosis and treatment for diabetes mellitus therapy. Copyright © 2016, American Association for the Advancement of Science.

  15. Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors.

    PubMed

    He, Rongjun; Yu, Zhi-Hong; Zhang, Ruo-Yu; Wu, Li; Gunawan, Andrea M; Lane, Brandon S; Shim, Joong S; Zeng, Li-Fan; He, Yantao; Chen, Lan; Wells, Clark D; Liu, Jun O; Zhang, Zhong-Yin

    2015-07-09

    Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.

  16. Mechanisms of antileukemic activity of the novel BH3 mimetic GX15-070 (obatoclax)

    PubMed Central

    Konopleva, Marina; Watt, Julie; Contractor, Rooha; Tsao, Twee; Harris, David; Estrov, Zeev; Bornmann, William; Kantarjian, Hagop; Viallet, Jean; Samudio, Ismael; Andreeff, Michael

    2013-01-01

    In this study, we investigated the mechanism of apoptosis induction of obatoclax (GX15-070), a novel BH3 mimetic, in acute myeloid leukemia (AML) cell lines and primary AML samples. Obatoclax inhibited cell growth of HL-60, U937, OCI-AML3 and KG-1 cell lines. Apoptosis induction contributed to the observed antiproliferative effects at concentrations of this agent that mirror its affinity for antiapoptotic Bcl-2 proteins. We demonstrate that obatoclax can promote the release of cytochrome C from isolated leukemia cell mitochondria, and that apoptosis induced by this agent is preceded by the release of Bak from Mcl-1, liberation of Bim from both Bcl-2 and Mcl-1, and the formation of an active Bak/Bax complex. Notably, apoptosis was diminished, but not fully prevented, in the absence of Bak/Bax or Bim suggesting that obatoclax has additional targets that contribute to its cytotoxicity. At growth-inhibitory doses that did not induce apoptosis or decreased viability, obatoclax induced an S/G2 cell cycle block. Obatoclax induced apoptosis in AML CD34+ progenitor cells with an average IC50 of 3.59 +/− 1.23μM although clonogenicity was inhibited at concentrations of 75-100 nM. Obatoclax synergized with the novel BH3 mimetic ABT-737 to induce apoptosis in OCI-AML3 cells, and synergistically induced apoptosis in combination with AraC in leukemic cell lines and in primary AML samples. In conclusion, we show that obatoclax potently induces apoptosis and decreases leukemia cell proliferation and may be used in a novel therapeutic strategy for AML alone and in combination with other targeted agents and chemotherapeutics. PMID:18451169

  17. Sidedness of interfacial arginine residues and anti-atherogenicity of apolipoprotein A-I mimetic peptides

    PubMed Central

    Nayyar, Gaurav; Mishra, Vinod K.; Handattu, Shaila P.; Palgunachari, Mayakonda N.; Shin, Ronald; McPherson, David T.; Deivanayagam, Champion C. S.; Garber, David W.; Segrest, Jere P.; Anantharamaiah, G. M.

    2012-01-01

    To test the hypothesis that sidedness of interfacial arginine (Arg) in apoA-I mimetic peptides, similar to that observed in apoA-I (Bashtovyy, D. et al. 2011. Sequence conservation of apolipoprotein A-I affords novel insights into HDL structure-function. J. Lipid Res. 52: 435–450.), may be important for biological activity, we compared properties of 4F and analogs, [K4,15>R]4F and [K9,13>R]4F, with Lys>Arg substitutions on the right and left side, respectively, of the 4F amphipathic helix. Intraperitoneal administration of these peptides into female apoE null mice (n = 13 in each group) reduced en face lesions significantly compared with controls; 4F and [K4,15>R]4F were equally effective whereas [K9,13>R]4F was less effective. Turnover experiments indicated that [K4,15>R]4F reached the highest, whereas [K9,13>R]4F had the lowest, plasma peak levels with a similar half life as the [K4,15>R]4F analog. The half life of 4F was two times longer than the other two peptides. The order in their abilities to associate with HDL in human plasma, generation of apoA-I particles with pre-β mobility from isolated HDL, lipid associating ability, and sensitivity of lipid complexes to trypsin digestion was: 4F>[K4,15,>R]4F>[K9,13>R]4F. These studies support our hypothesis that the sidedness of interfacial Arg residues in the polar face of apoA-I mimetics results in differential biological properties. PMID:22377531

  18. Cytotoxic effects of SMAC-mimetic compound LCL161 in head and neck cancer cell lines.

    PubMed

    Brands, Roman C; Herbst, Franziska; Hartmann, Stefan; Seher, Axel; Linz, Christian; Kübler, Alexander C; Müller-Richter, Urs D A

    2016-12-01

    Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumor entities worldwide. Unfortunately, recent drug developments in other fields of oncology have yielded no efficacy in the treatment of oral squamous cell carcinoma. As a new starting point, we investigated the impact of Fas ligand (FasL) and the SMAC-mimetic compound LCL161 in mono- and combination treatment in HNSCC cell lines. Five different cell lines of HNSCC were treated with FasL and LCL161 in mono- and combination treatment. Cytotoxicity was measured via a crystal violet assay. The cell lines were characterized for CD95 (FasL receptor) expression via flow cytometry. The degradation of cellular inhibitor of apoptosis protein 1 (cIAP1) was detected via Western blot. Incubation with FasL led to a significant decrease in three out of five cell lines. Combination treatment with LCL161 enhanced cytotoxicity significantly. Two cell lines were FasL resistant, but one of them could be resensitized with LCL161. In all cell lines, Western blot analysis showed degradation of cIAP1 after LCL161 application. However, one cell line showed only minor vulnerability to the FasL and LCL161 combination. This is the first study investigating combination treatment of FasL and LCL161 in head and neck cancer cell lines. Pro-apoptotic effects of the combination were detected in the majority of the cell lines. Interestingly, one of two FasL-resistant cell lines was sensitive to the combination therapy with FasL and LCL161. SMAC-mimetic compounds show promising results in the treatment of other tumor entities in vitro and might be useful drugs to improve HNSCC therapy.

  19. Pharmacology of smac mimetics; chemotype differentiation based on physical association with caspase regulators and cellular transport.

    PubMed

    Talbott, Randy L; Borzilleri, Robert M; Chaudhry, Charu; Fargnoli, Joseph; Shen, Henry; Fairchild, Craig; Barnhart, Bryan; Ortega, Marie; McDonagh, Thomas E; Vuppugalla, Ragini; Vite, Gregory D; Hunt, John T; Gottardis, Marco; Naglich, Joseph G

    2015-11-01

    Cellular levels of inhibitor of apoptosis (IAP) proteins are elevated in multiple human cancers and their activities often play a part in promoting cancer cell survival by blocking apoptotic pathways, controlling signal transduction pathways and contributing to resistance. These proteins function through interactions of their BIR (baculoviral IAP repeat) protein domains with pathway components and these interactions are endogenously antagonized by Smac/Diablo (second mitochondrial activator of caspases/direct IAP binding protein with low isoelectric point). This report describes development of synthetic smac mimetics (SM) and compares their binding, antiproliferative and anti-tumor activities. All dimeric antagonists inhibit in vitro smac tetrapeptide binding to recombinant IAP proteins, rescue IAP-bound caspase-3 activity and show anti-proliferative activity against human A875 melanoma cells. One heterodimeric SM, SM3, binds tightly to IAP proteins in vitro and slowly dissociates (greater than two hours) from these protein complexes compared to the other antagonists. In addition, in vitro SM anti-proliferation potency is influenced by ABCB1 transporter (ATP-binding cassette, sub-family B; MDR1, P-gp) activities and one antagonist, SM5, does not appear to be an ABCB1 efflux pump substrate. All dimeric smac mimetics inhibit the growth of human melanoma A875 tumors implanted in athymic mice at well-tolerated doses. One antagonist, SM4, shows broad spectrum in vivo anti-tumor activity and modulates known pharmacodynamic markers of IAP antagonism. These data taken together demonstrate the range of diverse dimeric IAP antagonist activities and supports their potential as anticancer agents. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Smac mimetic triggers necroptosis in pancreatic carcinoma cells when caspase activation is blocked.

    PubMed

    Hannes, Sabine; Abhari, Behnaz Ahangarian; Fulda, Simone

    2016-09-28

    Evasion of apoptosis represents a key mechanism of treatment resistance of pancreatic cancer (PC) and contributes to the poor prognosis of this cancer type. Here, we report that induction of necroptosis is an alternative strategy to trigger programmed cell death in apoptosis-resistant PC cells. We show that the second mitochondrial activator of caspases (Smac) mimetic BV6 that antagonizes inhibitor of apoptosis (IAP) proteins induces necroptosis in PC cells in which apoptosis is blocked by the caspase inhibitor zVAD.fmk. Intriguingly, BV6 switches autocrine/paracrine production of tumor necrosis factor (TNF)α by PC cells into a death signal and also acts in concert with exogenously supplied TNFα to trigger necroptosis, when caspase activation is simultaneously blocked. BV6 stimulates TNFα production and formation of the receptor-interacting protein (RIP)1/RIP3-containing necrosome complex in PC cells. Knockdown of TNF receptor 1 (TNFR1) protects PC cells from BV6- or BV6/TNFα-mediated cell death, demonstrating that TNFα autocrine/paracrine signaling by PC cells contributes to BV6-induced necroptosis. Importantly, genetic silencing of receptor interacting protein kinase 3 (RIPK3) or mixed lineage kinase domain-like protein (MLKL) significantly rescues PC cells from BV6- or BV6/TNFα-induced cell death. Similarly, pharmacological inhibition of RIP1, RIP3 or MLKL significantly reduces BV6- or BV6/TNFα-stimulated cell death. By demonstrating that Smac mimetics can bypass resistance to apoptosis by triggering necroptosis as an alternative form of programmed cell death, our findings have important implications for the design of new treatment concepts for PC. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  1. A novel approach to oral apoA-I mimetic therapy[S

    PubMed Central

    Chattopadhyay, Arnab; Navab, Mohamad; Hough, Greg; Gao, Feng; Meriwether, David; Grijalva, Victor; Springstead, James R.; Palgnachari, Mayakonda N.; Namiri-Kalantari, Ryan; Su, Feng; Van Lenten, Brian J.; Wagner, Alan C.; Anantharamaiah, G. M.; Farias-Eisner, Robin; Reddy, Srinivasa T.; Fogelman, Alan M.

    2013-01-01

    Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR−/−) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy. PMID:23378594

  2. Structural origins of the insulin-mimetic activity of bis(acetylacetonato)oxovanadium(IV).

    PubMed

    Makinen, Marvin W; Brady, Matthew J

    2002-04-05

    We have investigated the interaction of bis(acetylacetonato)oxovanadium(IV) (VO(acac)(2)) with bovine serum albumin (BSA) by EPR and angle-selected electron nuclear double resonance, correlating results with assays of glucose uptake by 3T3-L1 adipocytes. EPR spectra of VO(acac)(2) showed no broadening in the presence of BSA; however, electron nuclear double resonance titrations of VO(acac)(2) in the presence of BSA were indicative of adduct formation of VO(acac)(2) with albumin of 1:1 stoichiometry. The influence of VO(acac)(2) on uptake of 2-deoxy-d-[1-(14)C]glucose by serum-starved 3T3-L1 adipocytes was measured in the presence and absence of BSA. Glucose uptake was stimulated 9-fold in the presence of 0.5 mm VO(acac)(2), 17-fold in the presence of 0.5 mm VO(acac)(2) plus 1 mm BSA, and 22-fold in the presence of 100 nm insulin. BSA had no influence on glucose uptake, on the action of insulin, or on glucose uptake in the presence of VOSO(4). The maximum insulin-mimetic effect of VO(acac)(2) was observed at VO(acac)(2):BSA ratios less than or equal to 1.0. Similar results were obtained also with bis(maltolato)oxovanadium(IV). These results suggest that the enhanced insulin-mimetic action of organic chelates of VO(2+) may be dependent on adduct formation with BSA and possibly other serum transport proteins.

  3. Synthesis, characterisation and insulin-mimetic activity of oxovanadium(IV) complexes with amidrazone derivatives.

    PubMed

    Cocco, Maria Teresa; Onnis, Valentina; Ponticelli, Gustavo; Meier, Beate; Rehder, Dieter; Garribba, Eugenio; Micera, Giovanni

    2007-01-01

    The complexation of VO(2+) ion by ten acetamidrazone and 2-phenylacetamidrazone derivatives (L) was studied. Sixteen novel VO(2+) complexes were synthesised and characterised through the combined application of analytical and spectroscopic (EPR (electron paramagnetic resonance), FT-IR and diffuse reflectance electronic absorption) techniques. Eight are 1:2 species of composition [VOL(2)]SO(4) x xH(2)O and eight are 1:1 species with formula [VOL(SO(4))](n) x xH(2)O. The experimental data suggest a bidentate coordination mode for L with the donor set formed by the imine nitrogen and the carbonyl oxygen. EPR spectra indicate a square-pyramidal geometry for the 1:1 complexes and a penta-coordinated geometry intermediate between the square-pyramid and the trigonal-bipyramid for the 1:2 species. The hyperfine coupling constant along z axis, A(z), of the 1:2 complexes exhibits a marked reduction with respect to the predicted value (approximately 148x10(-4)cm(-1) vs. approximately 170x10(-4)cm(-1)). IR spectroscopic evidence supports the presence of sulphate as a counter-ion in the 1:2, and as a bridging bidentate ligand in the 1:1 complexes. Insulin-mimetic tests on modified fibroblasts, based on a modified MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazoliumbromide) assay, performed on three of the bis-chelated and eight of the mono-chelated derivatives, indicate that they are biologically active. The similar hydro/lipophilicity and the lack of ligand substituents recognizable by cell membrane receptors prevent substantial differentiation in the insulin-mimetic action.

  4. Solution NMR of SNAREs, complexin and α-synuclein in association with membrane-mimetics.

    PubMed

    Liang, Binyong; Tamm, Lukas K

    2018-04-01

    SNARE-mediated membrane fusion is a ubiquitous process responsible for intracellular vesicle trafficking, including membrane fusion in exocytosis that leads to hormone and neurotransmitter release. The proteins that facilitate this process are highly dynamic and adopt multiple conformations when they interact with other proteins and lipids as they form highly regulated molecular machines that operate on membranes. Solution NMR is an ideal method to capture high-resolution glimpses of the molecular transformations that take place when these proteins come together and work on membranes. Since solution NMR has limitations on the size of proteins and complexes that can be studied, lipid bilayer model membranes cannot be used in these approaches, so the relevant interactions are typically studied in various types of membrane-mimetics that are tractable by solution NMR methods. In this review we therefore first summarize different membrane-mimetic systems that are commonly used or that show promise for solution NMR studies of membrane-interacting proteins. We then summarize recent NMR studies on two SNARE proteins, syntaxin and synaptobrevin, and two related regulatory proteins, complexin and α-synuclein, and their interactions with membrane lipids. These studies provide a structural and dynamical framework for how these proteins might carry out their functions in the vicinity of lipid membranes. The common theme throughout these studies is that membrane interactions have major influences on the structural dynamics of these proteins that cannot be ignored when attempting to explain their functions in contemporary models of SNARE-mediated membrane fusion. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice

    PubMed Central

    Aslam, Mohamad F.; Frazer, David M.; Faria, Nuno; Bruggraber, Sylvaine F. A.; Wilkins, Sarah J.; Mirciov, Cornel; Powell, Jonathan J.; Anderson, Greg J.; Pereira, Dora I. A.

    2014-01-01

    The ferritin core is composed of fine nanoparticulate Fe3+ oxohydroxide, and we have developed a synthetic mimetic, nanoparticulate Fe3+ polyoxohydroxide (nanoFe3+). The aim of this study was to determine how dietary iron derived in this fashion is absorbed in the duodenum. Following a 4 wk run-in on an Fe-deficient diet, mice with intestinal-specific disruption of the Fpn-1 gene (Fpn-KO), or littermate wild-type (WT) controls, were supplemented with Fe2+ sulfate (FeSO4), nanoFe3+, or no added Fe for a further 4 wk. A control group was Fe sufficient throughout. Direct intestinal absorption of nanoFe3+ was investigated using isolated duodenal loops. Our data show that FeSO4 and nanoFe3+ are equally bioavailable in WT mice, and at wk 8 the mean ± sem hemoglobin increase was 18 ± 7 g/L in the FeSO4 group and 30 ± 5 g/L in the nanoFe3+ group. Oral iron failed to be utilized by Fpn-KO mice and was retained in enterocytes, irrespective of the iron source. In summary, although nanoFe3+ is taken up directly by the duodenum its homeostasis is under the normal regulatory control of dietary iron absorption, namely via ferroportin-dependent efflux from enterocytes, and thus offers potential as a novel oral iron supplement.—Aslam, M. F., Frazer, D. M., Faria, N., Bruggraber, S. F. A., Wilkins, S. J., Mirciov, C., Powell, J. J., Anderson, G. J., Pereira, D. I. A. Ferroportin mediates the intestinal absorption of iron from a nanoparticulate ferritin core mimetic in mice. PMID:24776745

  6. A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria.

    PubMed

    Wang, Xuefeng; Zhang, Chen; Yan, Xiangming; Lan, Bin; Wang, Jianyong; Wei, Chongyang; Cao, Xingxin; Wang, Renxiao; Yao, Jianhua; Zhou, Tao; Zhou, Mi; Liu, Qiaoling; Jiang, Biao; Jiang, Pengfei; Kesari, Santosh; Lin, Xinjian; Guo, Fang

    2016-03-15

    Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing antiapoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated. Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by high-performance liquid chromatography, and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin, and ABT-263 was also evaluated in colon cancer xenograft models and experimental liver metastasis models. Ch282-5 showed antiproliferative and pro-cell death activity against colon cancer cells both in vitro and in vivo, and the response to the drug correlated with inhibition of antiapoptotic Bcl-2 proteins, induction of mitochondria-dependent apoptotic pathway, and disruption of mitophagy and mTOR pathway. Ch282-5 also suppressed liver metastasis produced by intrasplenic injection of colon cancer cells. Furthermore, ch282-5 could potentiate the effectiveness of oxaliplatin and rescue ABT-263 efficacy by downregulation of Mcl-1 and elevation of platelet number. These findings provide a rational basis for clinical investigation of this highly promising BH3 mimetic in colon cancer. ©2015 American Association for Cancer Research.

  7. Cooperative TRAIL production mediates IFNα/Smac mimetic-induced cell death in TNFα-resistant solid cancer cells.

    PubMed

    Roesler, Stefanie; Eckhardt, Ines; Wolf, Sebastian; Fulda, Simone

    2016-01-26

    Smac mimetics antagonize IAP proteins, which are highly expressed in several cancers. Recent reports indicate that Smac mimetics trigger a broad cytokine response and synergize with immune modulators to induce cell death. Here, we identify a differential requirement of TRAIL or TNFα as mediators of IFNα/Smac mimetic-induced cell death depending on the cellular context. Subtoxic concentrations of Smac mimetics cooperate with IFNα to induce cell death in various solid tumor cell lines in a highly synergistic manner as determined by combination index. Mechanistic studies show that IFNα/BV6 cotreatment promotes the formation of a caspase-8-activating complex together with the adaptor protein FADD and RIP1. Assembly of this RIP1/FADD/caspase-8 complex represents a critical event, since RIP1 silencing inhibits IFNα/BV6-induced cell death. Strikingly, pharmacological inhibition of paracrine/autocrine TNFα signaling by the TNFα scavenger Enbrel rescues HT-29 colon carcinoma cells, but not A172 glioblastoma cells from IFNα/BV6-induced cell death. By comparison, A172 cells are significantly protected against IFNα/BV6 treatment by blockage of TRAIL signaling through genetic silencing of TRAIL or its cognate receptor TRAIL receptor 2 (DR5). Despite this differential requirement of TNFα and TRAIL signaling, mRNA and protein expression is increased by IFNα/BV6 cotreatment in both cell lines. Interestingly, A172 cells turn out to be resistant to exogenously added recombinant TNFα even in the presence of BV6, whereas they display a high sensitivity towards TRAIL/BV6. In contrast, BV6 efficiently sensitizes HT-29 cells to TNFα while TRAIL only had limited efficacy. This demonstrates that a differential sensitivity towards TRAIL or TNFα determines the dependency on either death receptor ligand for IFNα/Smac mimetic-induced cell death. Thus, by concomitant stimulation of both death receptor systems IFNα/Smac mimetic combination treatment is an effective strategy to

  8. Cholesterol depletion blocks redistribution of lipid raft components and insulin-mimetic signaling by glimepiride and phosphoinositolglycans in rat adipocytes.

    PubMed Central

    Müller, Gunter; Hanekop, Nils; Wied, Susanne; Frick, Wendelin

    2002-01-01

    Glycosylphosphatidylinositol-anchored plasma membrane (GPI) proteins, such as Gce1, the dually acylated nonreceptor tyrosine kinases (NRTKs), such as pp59(Lyn), and the membrane protein, caveolin, together with cholesterol are typical components of detergent/carbonate-insoluble glycolipid-enriched raft domains (DIGs) in the plasma membrane of most eucaryotes. Previous studies demonstrated the dissociation from caveolin and concomitant redistribution from DIGs of Gce1 and pp59(Lyn) in rat adipocytes in response to four different insulin-mimetic stimuli, glimepiride, phosphoinositolglycans, caveolin-binding domain peptide, and trypsin/NaCl-treatment. We now characterized the structural basis for this dynamic of DIG components. MATERIALS AND METHODS: Carbonate extracts from purified plasma membranes of basal and stimulated adipocytes were analyzed by high-resolution sucrose gradient centrifugation. RESULTS: This process revealed the existence of two distinct species of detergent/carbonate-insoluble complexes floating at higher buoyant density and harboring lower amounts of cholesterol, caveolin, GPI proteins, and NRTKs (lcDIGs) compared to typical DIGs of high cholesterol content (hcDIGs). The four insulin-mimetic stimuli decreased by 40-70% and increased by 2.5- to 5-fold the amounts of GPI proteins and NRTKs at hcDIGs and lcDIGs, respectively. Cholesterol depletion of adipocytes per se by incubation with methyl-beta-cyclodextrin or cholesterol oxidase also caused translocation of GPI proteins and NRTKs from hcDIGs to lcDIGs and their release from caveolin in reversible fashion without concomitant induction of insulin-mimetic signaling. Cholesterol depletion, however, reduced by 50-60% the stimulus-induced translocation as well as dissociation from hcDIGs-associated caveolin of GPI proteins and NRTKs, activation of NRTKs as well as insulin-mimetic signaling and metabolic action. In contrast, insulin-mimetic signaling induced by vanadium compounds was not

  9. Cholesterol depletion blocks redistribution of lipid raft components and insulin-mimetic signaling by glimepiride and phosphoinositolglycans in rat adipocytes.

    PubMed

    Müller, Gunter; Hanekop, Nils; Wied, Susanne; Frick, Wendelin

    2002-03-01

    Glycosylphosphatidylinositol-anchored plasma membrane (GPI) proteins, such as Gce1, the dually acylated nonreceptor tyrosine kinases (NRTKs), such as pp59(Lyn), and the membrane protein, caveolin, together with cholesterol are typical components of detergent/carbonate-insoluble glycolipid-enriched raft domains (DIGs) in the plasma membrane of most eucaryotes. Previous studies demonstrated the dissociation from caveolin and concomitant redistribution from DIGs of Gce1 and pp59(Lyn) in rat adipocytes in response to four different insulin-mimetic stimuli, glimepiride, phosphoinositolglycans, caveolin-binding domain peptide, and trypsin/NaCl-treatment. We now characterized the structural basis for this dynamic of DIG components. Carbonate extracts from purified plasma membranes of basal and stimulated adipocytes were analyzed by high-resolution sucrose gradient centrifugation. This process revealed the existence of two distinct species of detergent/carbonate-insoluble complexes floating at higher buoyant density and harboring lower amounts of cholesterol, caveolin, GPI proteins, and NRTKs (lcDIGs) compared to typical DIGs of high cholesterol content (hcDIGs). The four insulin-mimetic stimuli decreased by 40-70% and increased by 2.5- to 5-fold the amounts of GPI proteins and NRTKs at hcDIGs and lcDIGs, respectively. Cholesterol depletion of adipocytes per se by incubation with methyl-beta-cyclodextrin or cholesterol oxidase also caused translocation of GPI proteins and NRTKs from hcDIGs to lcDIGs and their release from caveolin in reversible fashion without concomitant induction of insulin-mimetic signaling. Cholesterol depletion, however, reduced by 50-60% the stimulus-induced translocation as well as dissociation from hcDIGs-associated caveolin of GPI proteins and NRTKs, activation of NRTKs as well as insulin-mimetic signaling and metabolic action. In contrast, insulin-mimetic signaling induced by vanadium compounds was not significantly diminished by cholesterol

  10. Smac Mimetic Bypasses Apoptosis Resistance in FADD- or Caspase-8-Deficient Cells by Priming for Tumor Necrosis Factor α-Induced Necroptosis12

    PubMed Central

    Laukens, Bram; Jennewein, Claudia; Schenk, Barbara; Vanlangenakker, Nele; Schier, Alexander; Cristofanon, Silvia; Zobel, Kerry; Deshayes, Kurt; Vucic, Domagoj; Jeremias, Irmela; Bertrand, Mathieu JM; Vandenabeele, Peter; Fulda, Simone

    2011-01-01

    Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance. PMID:22028622

  11. Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor α-induced necroptosis.

    PubMed

    Laukens, Bram; Jennewein, Claudia; Schenk, Barbara; Vanlangenakker, Nele; Schier, Alexander; Cristofanon, Silvia; Zobel, Kerry; Deshayes, Kurt; Vucic, Domagoj; Jeremias, Irmela; Bertrand, Mathieu J M; Vandenabeele, Peter; Fulda, Simone

    2011-10-01

    Searching for new strategies to bypass apoptosis resistance, we investigated the potential of the Smac mimetic BV6 in Jurkat leukemia cells deficient in key molecules of the death receptor pathway. Here, we demonstrate for the first time that Smac mimetic primes apoptosis-resistant, FADD- or caspase-8-deficient leukemia cells for TNFα-induced necroptosis in a synergistic manner. In contrast to TNFα, Smac mimetic significantly enhances CD95-induced apoptosis in wild-type but not in FADD-deficient cells. Interestingly, Smac mimetic- and TNFα-mediated cell death occurs without characteristic features of apoptosis (i.e., caspase activation, DNA fragmentation) in FADD-deficient cells. By comparison, Smac mimetic and TNFα trigger activation of caspase-8, -9, and -3 and DNA fragmentation in wild-type cells. Consistently, the caspase inhibitor zVAD.fmk fails to block Smac mimetic- and TNFα-triggered cell death in FADD- or caspase-8-deficient cells, while it confers protection in wild-type cells. By comparison, necrostatin-1, an RIP1 kinase inhibitor, abolishes Smac mimetic- and TNFα-induced cell death in FADD- or caspase-8-deficient. Thus, Smac mimetic enhances TNFα-induced cell death in leukemia cells via two distinct pathways in a context-dependent manner: it primes apoptosis-resistant cells lacking FADD or caspase-8 to TNFα-induced, RIP1-dependent and caspase-independent necroptosis, whereas it sensitizes apoptosis-proficient cells to TNFα-mediated, caspase-dependent apoptosis. These findings have important implications for the therapeutic exploitation of necroptosis as an alternative cell death program to overcome apoptosis resistance.

  12. Novel use of fluorescent glucose analogues to identify a new class of triazine-based insulin mimetics possessing useful secondary effects.

    PubMed

    Jung, Da-Woon; Ha, Hyung-Ho; Zheng, Xuexiu; Chang, Young-Tae; Williams, Darren R

    2011-02-01

    There is an urgent need to discover new compounds that effectively treat diabetes by mimicking the action of insulin (insulin mimetics). Traditional approaches to studying anti-diabetic agents in cells are inconvenient for screening chemical libraries to identify insulin mimetics. 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose (2-NBDG) and 6-NBDG are fluorescent analogues of glucose that could be employed in screening. However, there are no published data about the use of these analogues to identify new insulin mimetics. We have developed a screening system based on 6-NBDG using 3T3-L1 adipocytes in a 96-well culture plate format. 6-NBDG was found to produce a larger signal than 2-NBDG in this screening system. 6-NBDG uptake in 3T3-L1 adipocytes was sensitive to insulin, known insulin mimetics, inhibitors of glucose transport and insulin-sensitizing compounds. To validate our screening system, a chemical library of 576 tagged, triazine-based small molecules was screened. The screening results were identical to that obtained from a commercial enzyme-based glucose assay. Two inducers of glucose uptake were shown to be non-cytotoxic and confirmed as insulin mimetic compounds by their inhibition of epinephrine-stimulated free fatty acid release from adipocytes. These novel insulin mimetics functioned at a markedly lower concentration than two widely studied insulin mimetics, zinc(ii) complexes and vanadium compounds, and also showed novel, beneficial effects on endothelial cell function (a key determinant of secondary complications in diabetes). The discovery of new insulin mimetics using 6-NBDG validates the use of this probe in the development of large-scale, cell-based screening systems based on the uptake of fluorescent-tagged glucose analogues. This research should aid the development of novel strategies to discover new drugs and drug targets for combating the increasing prevalence of diabetes.

  13. 4-Connected azabicyclo[5.3.0]decane Smac mimetics-Zn2+ chelators as dual action antitumoral agents.

    PubMed

    Manzoni, Leonardo; Samela, Alessandro; Barbini, Stefano; Cairati, Silvia; Penconi, Marta; Arosio, Daniela; Lecis, Daniele; Seneci, Pierfausto

    2017-06-01

    Putative dual action compounds (DACs 3a-d) based on azabicyclo[5.3.0]decane (ABD) Smac mimetic scaffolds linked to Zn 2+ -chelating 2,2'-dipicolylamine (DPA) through their 4 position are reported and characterized. Their synthesis, their target affinity (cIAP1 BIR3, Zn 2+ ) in cell-free assays, their pro-apoptotic effects, and their cytotoxicity in tumor cells with varying sensitivity to Smac mimetics are described. A limited influence of Zn 2+ chelation on in vitro activity of DPA-substituted DACs 3a-d was sometimes perceivable, but did not lead to strong cellular synergistic effects. In particular, the linker connecting DPA with the ABD scaffold seems to influence cellular Zn 2+ -chelation, with longer lipophilic linkers/DAC 3c being the optimal choice. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Scaling mimesis: Morphometric and ecomorphological similarities in three sympatric plant-mimetic fish of the family Carangidae (Teleostei)

    PubMed Central

    de Queiroz, Alexya Cunha; Vallinoto, Marcelo; Sakai, Yoichi; Giarrizzo, Tommaso

    2018-01-01

    The mimetic juveniles of a number of carangid fish species resemble plant parts floating near the water surface, such as leaves, seeds and other plant debris. The present study is the first to verify the morphological similarities and ecomorphological relationships between three carangids (Oligoplites saurus, Oligoplites palometa and Trachinotus falcatus) and their associated plant models. Behavioral observations were conducted in the estuary of Curuçá River, in northeastern Pará (Brazil) between August 2015 and July 2016. Individual fishes and associated floating objects (models) were sampled for comparative analysis using both geometric and morphometric approaches. While the mimetic fish and their models retain their own distinct, intrinsic morphological features, a high degree of morphological similarity was found between each fish species and its model. The morphometric analyses revealed a general tendency of isometric development in all three fish species, probably related to their pelagic habitats, during all ontogenetic stages. PMID:29558476

  15. Scaling mimesis: Morphometric and ecomorphological similarities in three sympatric plant-mimetic fish of the family Carangidae (Teleostei).

    PubMed

    Queiroz, Alexya Cunha de; Vallinoto, Marcelo; Sakai, Yoichi; Giarrizzo, Tommaso; Barros, Breno

    2018-01-01

    The mimetic juveniles of a number of carangid fish species resemble plant parts floating near the water surface, such as leaves, seeds and other plant debris. The present study is the first to verify the morphological similarities and ecomorphological relationships between three carangids (Oligoplites saurus, Oligoplites palometa and Trachinotus falcatus) and their associated plant models. Behavioral observations were conducted in the estuary of Curuçá River, in northeastern Pará (Brazil) between August 2015 and July 2016. Individual fishes and associated floating objects (models) were sampled for comparative analysis using both geometric and morphometric approaches. While the mimetic fish and their models retain their own distinct, intrinsic morphological features, a high degree of morphological similarity was found between each fish species and its model. The morphometric analyses revealed a general tendency of isometric development in all three fish species, probably related to their pelagic habitats, during all ontogenetic stages.

  16. A Small Molecule Mimetic of the Humanin Peptide as a Candidate for Modulating NMDA-Induced Neurotoxicity.

    PubMed

    Alam, Mohammad Parvez; Bilousova, Tina; Spilman, Patricia; Vadivel, Kanagasabai; Bai, Dongsheng; Elias, Chris J; Evseenko, Denis; John, Varghese

    2018-03-21

    Humanin (HN), a 24-amino acid bioactive peptide, has been shown to increase cell survival of neurons after exposure to Aβ and NMDA-induced toxicity and thus could be beneficial in the treatment of Alzheimer's disease (AD). The neuroprotection by HN is reported to be primarily through its agonist binding properties to the gp130 receptor. However, the peptidic nature of HN presents challenges in its development as a therapeutic for AD. We report here for the first time the elucidation of the binding site of Humanin (HN) peptide to the gp130 receptor extracellular domain through modeling and the synthesis of small molecule mimetics that interact with the HN binding site on the gp130 receptor and provide protection against NMDA-induced neurotoxicity in primary hippocampal neurons. A brain permeable small molecule mimetic was identified through exploratory medicinal chemistry using microfluidic flow chemistry to facilitate the synthesis of new analogues for screening and SAR optimization.

  17. The arbitrary order mimetic finite difference method for a diffusion equation with a non-symmetric diffusion tensor

    DOE PAGES

    Gyrya, V.; Lipnikov, K.

    2017-07-18

    Here, we present the arbitrary order mimetic finite difference (MFD) discretization for the diffusion equation with non-symmetric tensorial diffusion coefficient in a mixed formulation on general polygonal meshes. The diffusion tensor is assumed to be positive definite. The asymmetry of the diffusion tensor requires changes to the standard MFD construction. We also present new approach for the construction that guarantees positive definiteness of the non-symmetric mass matrix in the space of discrete velocities. The numerically observed convergence rate for the scalar quantity matches the predicted one in the case of the lowest order mimetic scheme. For higher orders schemes, wemore » observed super-convergence by one order for the scalar variable which is consistent with the previously published result for a symmetric diffusion tensor. The new scheme was also tested on a time-dependent problem modeling the Hall effect in the resistive magnetohydrodynamics.« less

  18. A highly efficient type I β-turn mimetic simulating an Asx-Pro-turn-like structure.

    PubMed

    Pinsker, Andrea; Einsiedel, Jürgen; Härterich, Steffen; Waibel, Reiner; Gmeiner, Peter

    2011-07-01

    Asx-Pro-turns have been identified with high frequency in protein structures nucleating type I β-turns. By bridging the amino acid side chain in position i with a nitrogen substituent in position i+2 by ring-closing olefin metathesis (RCM), peptide mimetics of type 1 could be developed. NMR based conformational investigations indicated a stable intramolecular H-bond constraining a U-turn conformation that was predicted to simulate a type I β-turn.

  19. Arginine mimetics using α-guanidino acids: introduction of functional groups and stereochemistry adjacent to recognition guanidiniums in peptides.

    PubMed

    Balakrishnan, Shalini; Scheuermann, Michael J; Zondlo, Neal J

    2012-01-23

    Arginine residues are broadly employed for specific biomolecular recognition, including in protein-protein, protein-DNA, and protein-RNA interactions. Arginine recognition commonly exploits the potential for bidentate electrostatic and hydrogen-bonding interactions. However, in arginine residues, the guanidinium functional group is located at the terminus of a flexible hydrocarbon side chain, which lacks the functionality to contribute to specific arginine-mediated recognition and may entropically disfavor binding. In order to enhance the potential for specificity and affinity in arginine-mediated molecular recognition, we have developed an approach to the synthesis of peptides that incorporates an α-guanidino acid as a novel arginine mimetic. α-Guanidino acids, derived from α-amino acids, with guanidinylation of the amino group, were incorporated stereospecifically into peptides on solid phase via coupling of an Fmoc amino acid to diaminopropionic acid (Dap), Fmoc deprotection, guanidinylation of the amine on solid phase, and deprotection, generating a peptide containing an α-functionalized arginine mimetic. This approach was examined by incorporating arginine mimetics into ligands for the Src, Grb, and Crk SH3 domains at the site of the key recognition arginine. Protein binding was examined for peptides containing guanidino acids derived from Gly, L-Val, L-Phe, L-Trp, D-Val, D-Phe, and D-Trp. We demonstrate that paralogue specificity and target site affinity may be modulated with the use of α-guanidino acid-derived arginine mimetics, generating peptides that exhibit enhanced Src specificity by selection against Grb and peptides that reverse the specificity of the native peptide ligand, with enhancements in Src target specificity of up to 15-fold (1.6 kcal mol(-1)). Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  20. The Targeted SMAC Mimetic SW IV-134 is a strong enhancer of standard chemotherapy in pancreatic cancer.

    PubMed

    Hashim, Yassar M; Vangveravong, Suwanna; Sankpal, Narendra V; Binder, Pratibha S; Liu, Jingxia; Goedegebuure, S Peter; Mach, Robert H; Spitzer, Dirk; Hawkins, William G

    2017-01-17

    Pancreatic cancer is a lethal malignancy that frequently acquires resistance to conventional chemotherapies often associated with overexpression of inhibitors of apoptosis proteins (IAPs). We have recently described a novel means to deliver second mitochondria-derived activator of caspases (SMAC) mimetics selectively to cancer cells employing the sigma-2 ligand/receptor interaction. The intrinsic death pathway agonist SMAC offers an excellent opportunity to counteract the anti-apoptotic activity of IAPs. SMAC mimetics have been used to sensitize several cancer types to chemotherapeutic agents but cancer-selective delivery and appropriate cellular localization have not yet been considered. In our current study, we tested the ability of the sigma-2/SMAC drug conjugate SW IV-134 to sensitize pancreatic cancer cells to gemcitabine. Using the targeted SMAC mimetic SW IV-134, inhibition of the X-linked inhibitor of apoptosis proteins (XIAP) was induced pharmacologically and its impact on cell viability was studied alone and in combination with gemcitabine. Pathway analyses were performed by assessing caspase activation, PARP cleavage and membrane blebbing (Annexin-V), key components of apoptotic cell death. Single-agent treatment regimens were compared with combination therapy in a preclinical mouse model of pancreatic cancer. The sensitizing effect of XIAP interference toward gemcitabine was confirmed via pharmacological intervention using our recently designed, targeted SMAC mimetic SW IV-134 across a wide range of commonly used pancreatic cancer cell lines at concentrations where the individual drugs showed only minimal activity. On a mechanistic level, we identified involvement of key components of the apoptosis machinery during cell death execution. Furthermore, combination therapy proved superior in decreasing the tumor burden and extending the lives of the animals in a preclinical mouse model of pancreatic cancer. We believe that the strong sensitizing capacity of

  1. Targeting of apoptotic pathways by SMAC or BH3 mimetics distinctly sensitizes paclitaxel-resistant triple negative breast cancer cells.

    PubMed

    Panayotopoulou, Effrosini G; Müller, Anna-Katharina; Börries, Melanie; Busch, Hauke; Hu, Guohong; Lev, Sima

    2017-07-11

    Standard chemotherapy is the only systemic treatment for triple-negative breast cancer (TNBC), and despite the good initial response, resistance remains a major therapeutic obstacle. Here, we employed a High-Throughput Screen to identify targeted therapies that overcome chemoresistance in TNBC. We applied short-term paclitaxel treatment and screened 320 small-molecule inhibitors of known targets to identify drugs that preferentially and efficiently target paclitaxel-treated TNBC cells. Among these compounds the SMAC mimetics (BV6, Birinapant) and BH3-mimetics (ABT-737/263) were recognized as potent targeted therapy for multiple paclitaxel-residual TNBC cell lines. However, acquired paclitaxel resistance through repeated paclitaxel pulses result in desensitization to BV6, but not to ABT-263, suggesting that short- and long-term paclitaxel resistance are mediated by distinct mechanisms. Gene expression profiling of paclitaxel-residual, -resistant and naïve MDA-MB-231 cells demonstrated that paclitaxel-residual, as opposed to -resistant cells, were characterized by an apoptotic signature, with downregulation of anti-apoptotic genes (BCL2, BIRC5), induction of apoptosis inducers (IL24, PDCD4), and enrichment of TNFα/NF-κB pathway, including upregulation of TNFSF15, coupled with cell-cycle arrest. BIRC5 and FOXM1 downregulation and IL24 induction was also evident in breast cancer patient datasets following taxane treatment. Exposure of naïve or paclitaxel-resistant cells to supernatants of paclitaxel-residual cells sensitized them to BV6, and treatment with TNFα enhanced BV6 potency, suggesting that sensitization to BV6 is mediated, at least partially, by secreted factor(s). Our results suggest that administration of SMAC or BH3 mimetics following short-term paclitaxel treatment could be an effective therapeutic strategy for TNBC, while only BH3-mimetics could effectively overcome long-term paclitaxel resistance.

  2. SOD mimetics: A Novel Class of Androgen Receptor Inhibitors that Suppresses Castration-Resistant Growth of Prostate Cancer

    PubMed Central

    Thomas, Rusha; Sharifi, Nima

    2011-01-01

    Advanced prostate cancer (PCa) is the second-leading cause of cancer-related deaths among American men. The androgen receptor (AR) is vital for PCa progression, even in the face of castrate levels of serum testosterone following androgen ablation therapy, a mainstay therapy for advanced PCa. Downregulation of superoxide dismutase 2 (SOD2), a major intracellular antioxidant enzyme, occurs progressively during PCa progression to advanced states, and is known to promote AR activity in PCa. Therefore, this study investigated the effects of SOD mimetics on AR expression and function in AR-dependent LNCaP, CWR22Rv1, and LAPC-4AD PCa cells. Treatment with Tempol, a SOD mimetic, not only lowered cellular superoxide levels, but also concomitantly attenuated AR transcriptional activity and AR target gene expression in a dose- and time-dependent manner, in the presence and absence of dihydrotestosterone, the major endogenous AR agonist. Tempol's inhibition of AR was mediated, in large part, by its ability to decrease AR protein via increased degradation, in the absence of any inhibitory effects on other nuclear receptors. Tempol's inhibitory effects on AR were also reproducible with other SOD mimetics, MnTBAP and MnTMPyP. Importantly, Tempol's effects on AR function were accompanied by significant in vitro and in vivo reduction in castration-resistant PCa survival and growth. Collectively, this study has demonstrated for the first time that SOD mimetics, by virtue of their ability to suppress AR function, may be beneficial in treating the currently incurable castration-resistant PCa in which SOD2 expression is highly suppressed. PMID:22172488

  3. Superior peroxidase mimetic activity of tungsten disulfide nanosheets/silver nanoclusters composite: Colorimetric, fluorometric and electrochemical studies.

    PubMed

    Khataee, Alireza; Haddad Irani-Nezhad, Mahsa; Hassanzadeh, Javad; Woo Joo, Sang

    2018-04-01

    Developing a novel peroxidase nano-mimetic is a challenging research topic in biosensing field. Herein, WS 2 nanosheets (WS 2 NS) decorated with silver nanoclusters (AgNCs) was introduced as a new nanocomposite with improved peroxidase mimetic behavior. WS 2 NS/AgNCs nanocomposite was synthesized by simple chemical reduction of silver cations in the presence of WS 2 NS. The enhanced catalytic activity of nanocomposite in chemical and electrochemical reduction of H 2 O 2 was studied using colorimetry, fluorometry and electrochemical techniques. Attaching the AgNCs on the surface of WS 2 NS effectively improved the catalytic activity of these nanosheets, which may be connected to the difference of the Fermi energy levels of coupled nanomaterial. The unequal Fermi levels cause charge separation between two phases creating highly active sites on the interface of coupled nanomaterial. Moreover, the new mimetic nanocomposite was applied for the analysis of glucose in blood, based on its enzymatic oxidation using glucose oxidase and then, on the measurement of produced H 2 O 2 by sensitive fluorescence detection system. In optimum condition, a linear association was found between the generated fluorescence intensity and glucose logarithmic concentration in the range of 0.05-400 µM, and the limit of detection (3S/m) was 21 nM. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Systematic Computation of Nonlinear Cellular and Molecular Dynamics with Low-Power CytoMimetic Circuits: A Simulation Study

    PubMed Central

    Papadimitriou, Konstantinos I.; Stan, Guy-Bart V.; Drakakis, Emmanuel M.

    2013-01-01

    This paper presents a novel method for the systematic implementation of low-power microelectronic circuits aimed at computing nonlinear cellular and molecular dynamics. The method proposed is based on the Nonlinear Bernoulli Cell Formalism (NBCF), an advanced mathematical framework stemming from the Bernoulli Cell Formalism (BCF) originally exploited for the modular synthesis and analysis of linear, time-invariant, high dynamic range, logarithmic filters. Our approach identifies and exploits the striking similarities existing between the NBCF and coupled nonlinear ordinary differential equations (ODEs) typically appearing in models of naturally encountered biochemical systems. The resulting continuous-time, continuous-value, low-power CytoMimetic electronic circuits succeed in simulating fast and with good accuracy cellular and molecular dynamics. The application of the method is illustrated by synthesising for the first time microelectronic CytoMimetic topologies which simulate successfully: 1) a nonlinear intracellular calcium oscillations model for several Hill coefficient values and 2) a gene-protein regulatory system model. The dynamic behaviours generated by the proposed CytoMimetic circuits are compared and found to be in very good agreement with their biological counterparts. The circuits exploit the exponential law codifying the low-power subthreshold operation regime and have been simulated with realistic parameters from a commercially available CMOS process. They occupy an area of a fraction of a square-millimetre, while consuming between 1 and 12 microwatts of power. Simulations of fabrication-related variability results are also presented. PMID:23393550

  5. Collagen-binding VEGF mimetic peptide: Structure, matrix interaction, and endothelial cell activation

    NASA Astrophysics Data System (ADS)

    Chan, Tania R.

    Long term survival of artificial tissue constructs depends greatly on proper vascularization. In nature, differentiation of endothelial cells and formation of vasculature are directed by dynamic spatio-temporal cues in the extracellular matrix that are difficult to reproduce in vitro. In this dissertation, we present a novel bifunctional peptide that mimics matrix-bound vascular endothelial growth factor (VEGF), which can be used to encode spatially controlled angiogenic signals in collagen-based scaffolds. The peptide, QKCMP, contains a collagen mimetic domain (CMP) that binds to type I collagen by a unique triple helix hybridization mechanism and a VEGF mimetic domain (QK) with pro-angiogenic activity. We demonstrate QKCMP's ability to hybridize with native and heat denatured collagens through a series of binding studies on collagen and gelatin substrates. Circular dichroism experiments show that the peptide retains the triple helical structure vital for collagen binding, and surface plasmon resonance study confirms the molecular interaction between the peptide and collagen strands. Cell culture studies demonstrate QKCMP's ability to induce endothelial cell morphogenesis and network formation as a matrix-bound factor in 2D and 3D collagen scaffolds. We also show that the peptide can be used to spatially modify collagen-based substrates to promote localized endothelial cell activation and network formation. To probe the biological events that govern these angiogenic cellular responses, we investigated the cell signaling pathways activated by collagen-bound QKCMP and determined short and long-term endothelial cell response profiles for p38, ERK1/2, and Akt signal transduction cascades. Finally, we present our efforts to translate the peptide's in vitro bioactivity to an in vivo burn injury animal model. When implanted at the wound site, QKCMP functionalized biodegradable hydrogels induce enhanced neovascularization in the granulation tissue. The results show QKCMP

  6. Thioredoxin-mimetic peptide CB3 lowers MAPKinase activity in the Zucker rat brain☆

    PubMed Central

    Cohen-Kutner, Moshe; Khomsky, Lena; Trus, Michael; Ben-Yehuda, Hila; Lenhard, James M.; Liang, Yin; Martin, Tonya; Atlas, Daphne

    2014-01-01

    Diabetes is a high risk factor for dementia. High glucose may be a risk factor for dementia even among persons without diabetes, and in transgenic animals it has been shown to cause a potentiation of indices that are pre-symptomatic of Alzheimer's disease. To further elucidate the underlying mechanisms linking inflammatory events elicited in the brain during oxidative stress and diabetes, we monitored the activation of mitogen-activated kinsase (MAPKs), c-jun NH2-terminal kinase (JNK), p38 MAP kinases (p38MAPK), and extracellular activating kinsae1/2 (ERK1/2) and the anti-inflammatory effects of the thioredoxin mimetic (TxM) peptides, Ac-Cys-Pro-Cys-amide (CB3) and Ac-Cys-Gly-Pro-Cys-amide (CB4) in the brain of male leptin-receptor-deficient Zucker diabetic fatty (ZDF) rats and human neuroblastoma SH-SY5Y cells. Daily i.p. injection of CB3 to ZDF rats inhibited the phosphorylation of JNK and p38MAPK, and prevented the expression of thioredoxin-interacting-protein (TXNIP/TBP-2) in ZDF rat brain. Although plasma glucose/insulin remained high, CB3 also increased the phosphorylation of AMP-ribose activating kinase (AMPK) and inhibited p70S6K kinase in the brain. Both CB3 and CB4 reversed apoptosis induced by inhibiting thioredoxin reductase as monitored by decreasing caspase 3 cleavage and PARP dissociation in SH-SY5Y cells. The decrease in JNK and p38MAPK activity in the absence of a change in plasma glucose implies a decrease in oxidative or neuroinflammatory stress in the ZDF rat brain. CB3 not only attenuated MAPK phosphorylation and activated AMPK in the brain, but it also diminished apoptotic markers, most likely acting via the MAPK–AMPK–mTOR pathway. These results were correlated with CB3 and CB4 inhibiting inflammation progression and protection from oxidative stress induced apoptosis in human neuronal cells. We suggest that by attenuating neuro-inflammatory processes in the brain Trx1 mimetic peptides could become beneficial for preventing neurological

  7. Three-layer microfibrous peripheral nerve guide conduit composed of elastin-laminin mimetic artificial protein and poly(L-lactic acid)

    NASA Astrophysics Data System (ADS)

    Kakinoki, Sachiro; Nakayama, Midori; Moritan, Toshiyuki; Yamaoka, Tetsuji

    2014-07-01

    We developed a microfibrous poly(L-lactic acid) (PLLA) nerve conduit with a three-layered structure to simultaneously enhance nerve regeneration and prevent adhesion of surrounding tissue. The inner layer was composed of PLLA microfiber containing 25% elastin-laminin mimetic protein (AG73-(VPGIG)30) that promotes neurite outgrowth. The thickest middle layer was constructed of pure PLLA microfibers that impart the large mechanical stremgth to the conduit. A 10% poly(ethylene glycol) was added to the outer layer to prevent the adhesion with the surrounding tissue. The AG73-(VPGIG)30 composisting of an elastin-like repetitive sequence (VPGIG)30 and a laminin-derived sequence (RKRLQVQLSIRT: AG73) was biosynthesized using Escherichia coli. The PLLA microfibrous conduits were fabricated using an electrospinning procedure. AG73-(VPGIG)30 was successfully mixed in the PLLA microfibers, and the PLLA/AG73-(VPGIG)30 microfibers were stable under physiological conditions. The PLLA/AG73-(VPGIG)30 microfibers enhanced adhesion and neurite outgrowth of PC12 cells. The electrospun microfibrous conduit with a three-layered structure was implanted for bridging a 2.0-cm gap in the tibial nerve of a rabbit. Two months after implantation, no adhesion of surrounding tissue was observed, and the action potential was slightly improved in the nerve conduit with the PLLA/AG73-(VPGIG)30 inner layer.

  8. Three-layer microfibrous peripheral nerve guide conduit composed of elastin-laminin mimetic artificial protein and poly(L-lactic acid)

    PubMed Central

    Kakinoki, Sachiro; Nakayama, Midori; Moritan, Toshiyuki; Yamaoka, Tetsuji

    2014-01-01

    We developed a microfibrous poly(L-lactic acid) (PLLA) nerve conduit with a three-layered structure to simultaneously enhance nerve regeneration and prevent adhesion of surrounding tissue. The inner layer was composed of PLLA microfiber containing 25% elastin-laminin mimetic protein (AG73-(VPGIG)30) that promotes neurite outgrowth. The thickest middle layer was constructed of pure PLLA microfibers that impart the large mechanical strength to the conduit. A 10% poly(ethylene glycol) was added to the outer layer to prevent the adhesion with the surrounding tissue. The AG73-(VPGIG)30 compositing of an elastin-like repetitive sequence (VPGIG)30 and a laminin-derived sequence (RKRLQVQLSIRT: AG73) was biosynthesized using Escherichia coli. The PLLA microfibrous conduits were fabricated using an electrospinning procedure. AG73-(VPGIG)30 was successfully mixed in the PLLA microfibers, and the PLLA/AG73-(VPGIG)30 microfibers were stable under physiological conditions. The PLLA/AG73-(VPGIG)30 microfibers enhanced adhesion and neurite outgrowth of PC12 cells. The electrospun microfibrous conduit with a three-layered structure was implanted for bridging a 2.0-cm gap in the tibial nerve of a rabbit. Two months after implantation, no adhesion of surrounding tissue was observed, and the action potential was slightly improved in the nerve conduit with the PLLA/AG73-(VPGIG)30 inner layer. PMID:25101261

  9. Extreme Mechanical Behavior of Nacre-Mimetic Graphene-Oxide and Silk Nanocomposites.

    PubMed

    Xie, Wanting; Tadepalli, Sirimuvva; Park, Sang Hyun; Kazemi-Moridani, Amir; Jiang, Qisheng; Singamaneni, Srikanth; Lee, Jae-Hwang

    2018-02-14

    Biological materials have the ability to withstand extreme mechanical forces due to their unique multilevel hierarchical structure. Here, we fabricated a nacre-mimetic nanocomposite comprised of silk fibroin and graphene oxide that exhibits hybridized dynamic responses arising from alternating high-contrast mechanical properties of the components at the nanoscale. Dynamic mechanical behavior of these nanocomposites is assessed through a microscale ballistic characterization using a 7.6 μm diameter silica sphere moving at a speed of approximately 400 m/s. The volume fraction of graphene oxide in these composites is systematically varied from 0 to 32 vol % to quantify the dynamic effects correlating with the structural morphologies of the graphene oxide flakes. Specific penetration energy of the films rapidly increases as the distribution of graphene oxide flakes evolves from noninteracting, isolated sheets to a partially overlapping continuous sheet. The specific penetration energy of the nanocomposite at the highest graphene oxide content tested here is found to be significantly higher than that of Kevlar fabrics and close to that of pure multilayer graphene. This study evidently demonstrates that the morphologies of nanoscale constituents and their interactions are critical to realize scalable high-performance nanocomposites using typical nanomaterial constituents having finite dimensions.

  10. Interfacial cavity filling to optimize CD4-mimetic miniprotein interactions with the HIV-1 surface protein

    PubMed Central

    Morellato-Castillo, Laurence; Acharya, Priyamvada; Combes, Olivier; Michiels, Johan; Descours, Anne; Ramos, Oscar H. P.; Yang, Yongping; Vanham, Guido; Ariën, Kevin K.; Kwong, Peter D.; Martin, Loïc; Kessler, Pascal

    2013-01-01

    Ligand affinities can be optimized by interfacial cavity filling. A hollow (Phe43 cavity) between HIV-1 surface protein (gp120) and cluster of differentiation 4 (CD4) receptor, extends beyond residue phenylalanine 43 of CD4 and cannot be fully accessed by natural amino acids. To increase HIV-1 gp120 affinity for a family of CD4-mimetic miniproteins (miniCD4s), we targeted the gp120 Phe43 cavity with eleven non-natural phenylalanine derivatives, introduced into a miniCD4 named M48 (1). The best derivative named M48U12 (13) binds HIV-1 YU2 gp120 with 8 pM affinity, and shows potent HIV-1 neutralization. It contained a methylcyclohexyl derivative of 4-aminophenylalanine and its co-crystal structure with gp120 revealed the cyclohexane ring buried within the gp120 hydrophobic core but able to assume multiple orientations in the binding pocket, and an aniline nitrogen potentially providing a focus for further improvement. Altogether, the results provide a framework for filling the interfacial Phe43 cavity to enhance miniCD4 affinity. PMID:23710622

  11. Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats.

    PubMed

    Zhang, Ying; Cazakoff, Brittany N; Thai, Chester A; Howland, John G

    2012-03-01

    Current understanding of the etiology of neurodevelopmental disorders is limited; however, recent epidemiological studies demonstrate a strong correlation between prenatal infection during pregnancy and the development of schizophrenia in adult offspring. In particular, schizophrenia patients subjected to prenatal infection exhibit impairments in executive functions greater than schizophrenia patients not exposed to an infection while in utero. Acute prenatal treatment of rodents with the viral mimetic polyinosinic-polycytidylic acid (PolyI:C) induces behavioural and neuropathological alterations in the adult offspring similar to schizophrenia. However, impairments on tasks of executive function that involve the prefrontal cortex (PFC) have been rarely examined for the prenatal infection model. Hence, we investigated the effects of acute prenatal injection of PolyI:C (4.0 mg/kg, i.v., gestational day 15) on strategy set-shifting and reversal learning in an operant-based task. Our results show male, but not female, PolyI:C-treated adult offspring require more trials to reach criterion and perseverate during set-shifting. An opposite pattern was seen on the reversal day where the PolyI:C-treated male rats made fewer regressive errors. Females took more pre-training days and were slower to respond during the trials when compared to males regardless of prenatal treatment. The present findings validate the utility of the prenatal infection model for examining alterations of executive function, one of the most prominent cognitive symptoms of schizophrenia. Copyright © 2011 Elsevier Ltd. All rights reserved.

  12. Bacterial mimetics of endocrine secretory granules as immobilized in vivo depots for functional protein drugs

    PubMed Central

    Céspedes, María Virtudes; Fernández, Yolanda; Unzueta, Ugutz; Mendoza, Rosa; Seras-Franzoso, Joaquin; Sánchez-Chardi, Alejando; Álamo, Patricia; Toledo-Rubio, Verónica; Ferrer-Miralles, Neus; Vázquez, Esther; Schwartz, Simó; Abasolo, Ibane; Corchero, José Luis; Mangues, Ramon; Villaverde, Antonio

    2016-01-01

    In the human endocrine system many protein hormones including urotensin, glucagon, obestatin, bombesin and secretin, among others, are supplied from amyloidal secretory granules. These granules form part of the so called functional amyloids, which within the whole aggregome appear to be more abundant than formerly believed. Bacterial inclusion bodies (IBs) are non-toxic, nanostructured functional amyloids whose biological fabrication can be tailored to render materials with defined biophysical properties. Since under physiological conditions they steadily release their building block protein in a soluble and functional form, IBs are considered as mimetics of endocrine secretory granules. We have explored here if the in vivo implantation of functional IBs in a given tissue would represent a stable local source of functional protein. Upon intratumoral injection of bacterial IBs formed by a potent protein ligand of CXCR4 we have observed high stability and prevalence of the material in absence of toxicity, accompanied by apoptosis of CXCR4+ cells and tumor ablation. Then, the local immobilization of bacterial amyloids formed by therapeutic proteins in tumors or other tissues might represent a promising strategy for a sustained local delivery of protein drugs by mimicking the functional amyloidal architecture of the mammals’ endocrine system. PMID:27775083

  13. Non-Covalent Photo-Patterning of Gelatin Matrices Using Caged Collagen Mimetic Peptides

    PubMed Central

    Li, Yang; Hoa San, Boi; L. Kessler, Julian; Hwan Kim, Jin; Xu, Qingguo; Hanes, Justin; Yu, Seungju Michael

    2015-01-01

    Advancements in photolithography have enabled us to spatially encode biochemical cues in biocompatible platforms such as synthetic hydrogels. Conventional patterning works through photo-activated chemical reactions on inert polymer networks. However, these techniques cannot be directly applied to protein hydrogels without chemically altering the protein scaffolds. To this end, we developed a non-covalent photo-patterning strategy for gelatin (denatured collagen) hydrogels utilizing a caged collagen mimetic peptide (caged CMP) which binds to gelatin strands through UV activated, triple helix hybridization. Here we present 2D and 3D photo-patterning of gelatin hydrogels enabled by the caged CMPs as well as creation of concentration gradients of CMPs. We show that photo-patterning of PEG-conjugated caged CMPs can be used to spatially control cell adhesion on gelatin films. CMP’s specificity for binding to gelatin allows patterning of almost any synthetic or natural gelatin-containing matrix, such as zymograms, gelatin-methacrylate hydrogels, and even a corneal tissue. Since the CMP is a chemically and biologically inert peptide which is proven to be an ideal carrier for bioactive molecules, our patterning method provides a radically new tool for immobilizing drugs to natural tissues and for functionalizing scaffolds for complex tissue formation. PMID:25476588

  14. Tempol, a Superoxide Dismutase-Mimetic Drug, Ameliorates Progression of Renal Disease in CKD Mice.

    PubMed

    Ding, Wei; Wang, Bin; Zhang, Minmin; Gu, Yong

    2015-01-01

    Oxidative stress has been implicated in the pathogenesis of chronic kidney disease (CKD) and antioxidants may ameliorate disease progression. We investigate the beneficial effect of Tempol, a superoxide dismutase-mimetic drug, on progression of disease in a mouse model of CKD. CKD was surgically induced in c57BL/6 mice by 5/6 nephrectomy. Mice were randomly divided into 3 groups: sham group, 5/6 nephrectomized group (Nx) and Nx+Tempol (2 mmol/l in drinking water). Mice were sacrificed at the end of 12 weeks. Renal function, structure as well as expression of key molecules involved in the pathogenesis of inflammation, fibrosis and progression in mice were measured. Reduced body weight and impaired renal function (elevation on serum creatinine, blood urea nitrogen, urine albumin, segmental sclerosis and tubulointerstitial damage) was demonstrated in Nx mice but was significantly improved by Tempol administration. Nx animals exhibited significantly elevated proinflammatory and profibrotic factors, activation of NF-κB, increased expression of NADPH oxidase related subunits (p47phox, p67phox, gp91phox), and elevated activation of TGF-β/Smad3, EGFR, MAPK signaling pathway. Tempol inhibited NF-κB mediated inflammation, TGF-β/Smad3-induced renal fibrosis as well as EGFR and MAPK signaling pathway activation. Tempol administration attenuated renal injury in CKD mice through NF-κB, TGF-β/Smad3, redox-senstive EGFR activation and c-Raf/MEK/ERK pathways. © 2015 S. Karger AG, Basel.

  15. Efficacy of the superoxide dismutase mimetic tempol in animal hypertension models: a meta-analysis.

    PubMed

    Dornas, Waleska C; Silva, Maísa; Tavares, Ricardo; de Lima, Wanderson G; dos Santos, Rinaldo C; Pedrosa, Maria L; Silva, Marcelo E

    2015-01-01

    Considering the growing body of evidence that indicates the contribution of superoxide anions (O2) and other reactive oxygen species (ROS) to the development of hypertension, we assessed whether animal models of hypertension have a benefic effect with tempol, a superoxide dismutase mimetic, to help augment the design of future studies. Studies published between July 1998 and December 2012 on blood pressure (BP) in different hypertensive models were obtained after an electronic and manual search of PubMed. In-depth analyses of the methodological quality of the studies and the mean arterial pressure (MAP) changes after treatment with tempol were performed, as well as the subgroup analyses on the route of tempol delivery. Out of the 144 identified studies, 28 were included after screening. The data showed that tempol reduced MAP by computing the standardized mean difference with the value of 4.622 (95% confidence interval 3.24-5.99). The quality of studies included in the meta-analysis was category II; however, omission of details in the trials might have biased the results. There was substantial heterogeneity in the results with an I of 94.45%, which persisted after stratifying for the route of tempol delivery. In conclusion, this analysis shows that antioxidant treatment with tempol can reduce BP, suggesting that ROS plays a role in the pathogenesis of increased BP in the hypertension models used in the current research practice.

  16. Tempol, a Superoxide Dismutase Mimetic Agent, Inhibits Superoxide Anion-Induced Inflammatory Pain in Mice.

    PubMed

    Bernardy, Catia C F; Zarpelon, Ana C; Pinho-Ribeiro, Felipe A; Calixto-Campos, Cássia; Carvalho, Thacyana T; Fattori, Victor; Borghi, Sergio M; Casagrande, Rubia; Verri, Waldiceu A

    2017-01-01

    The present study evaluated the anti-inflammatory and analgesic effects of the superoxide dismutase mimetic agent tempol in superoxide anion-induced pain and inflammation. Mice were treated intraperitoneally with tempol (10-100 mg/kg) 40 min before the intraplantar injection of a superoxide anion donor, potassium superoxide (KO 2 , 30  μ g). Mechanical hyperalgesia and thermal hyperalgesia, paw edema, and mRNA expression of peripheral and spinal cord mediators involved in inflammatory pain, TNF α , IL-1 β , IL-10, COX-2, preproET-1, gp91 phox , Nrf2, GFAP, and Iba-1, were evaluated. Peripheral and spinal cord reductions of antioxidant defenses and superoxide anion were also assessed. Tempol reduced KO 2 -induced mechanical hyperalgesia and thermal hyperalgesia and paw edema. The increased mRNA expression of the evaluated mediators and oxidative stress in the paw skin and spinal cord and increased mRNA expression of glial markers in the spinal cord induced by KO 2 were successfully inhibited by tempol. KO 2 -induced reduction in Nrf2 mRNA expression in paw skin and spinal cord was also reverted by tempol. Corroborating the effect of tempol in the KO 2 model, tempol also inhibited carrageenan and CFA inflammatory hyperalgesia. The present study demonstrates that tempol inhibits superoxide anion-induced molecular and behavioral alterations, indicating that tempol deserves further preclinical studies as a promising analgesic and anti-inflammatory molecule for the treatment of inflammatory pain.

  17. Structurally Ordered Nanowire Formation from Co-Assembly of DNA Origami and Collagen-Mimetic Peptides

    DOE PAGES

    Jiang, Tao; Meyer, Travis A.; Modlin, Charles; ...

    2017-09-26

    In this paper, we describe the co-assembly of two different building units: collagen-mimetic peptides and DNA origami. Two peptides CP ++ and sCP ++ are designed with a sequence comprising a central block (Pro-Hyp-Gly) and two positively charged domains (Pro-Arg-Gly) at both N- and C-termini. Co-assembly of peptides and DNA origami two-layer (TL) nanosheets affords the formation of one-dimensional nanowires with repeating periodicity of similar to 10 nm. Structural analyses suggest a face-to-face stacking of DNA nanosheets with peptides aligned perpendicularly to the sheet surfaces. We demonstrate the potential of selective peptide-DNA association between face-to-face and edge-to-edge packing by tailoringmore » the size of DNA nanostructures. Finally, this study presents an attractive strategy to create hybrid biomolecular assemblies from peptide and DNA-based building blocks that takes advantage of the intrinsic chemical and physical properties of the respective components to encode structural and, potentially, functional complexity within readily accessible biomimetic materials.« less

  18. The mimetic transition: a simulation study of the evolution of learning by imitation.

    PubMed

    Higgs, P G

    2000-07-07

    Culturally transmitted ideas or memes must have had a large effect on the survival and fecundity of early humans. Those with better techniques of obtaining food and making tools, clothing and shelters would have had a substantial advantage. It has been proposed that memes can explain why our species has an unusually large brain and high cognitive ability: the brain evolved because of selection for the ability to imitate. This article presents an evolutionary model of a population in which culturally transmitted memes can have both positive and negative effects on the fitness of individuals. It is found that genes for increased imitative ability are selectively favoured. The model predicts that imitative ability increases slowly until a mimetic transition occurs where memes become able to spread like an epidemic. At this point there is a dramatic increase in the imitative ability, the number of memes known per individual and the mean fitness of the population. Selection for increased imitative ability is able to overcome substantial selection against increased brain size in some cases.

  19. The mimetic transition: a simulation study of the evolution of learning by imitation.

    PubMed Central

    Higgs, P G

    2000-01-01

    Culturally transmitted ideas or memes must have had a large effect on the survival and fecundity of early humans. Those with better techniques of obtaining food and making tools, clothing and shelters would have had a substantial advantage. It has been proposed that memes can explain why our species has an unusually large brain and high cognitive ability: the brain evolved because of selection for the ability to imitate. This article presents an evolutionary model of a population in which culturally transmitted memes can have both positive and negative effects on the fitness of individuals. It is found that genes for increased imitative ability are selectively favoured. The model predicts that imitative ability increases slowly until a mimetic transition occurs where memes become able to spread like an epidemic. At this point there is a dramatic increase in the imitative ability, the number of memes known per individual and the mean fitness of the population. Selection for increased imitative ability is able to overcome substantial selection against increased brain size in some cases. PMID:10972132

  20. History Matching for Fractured Reservoirs using Mimetic Finite Differences and Ensemble Kalman Filter

    NASA Astrophysics Data System (ADS)

    Min, B.; Ping, J.; Al-Hinai, O.; Srinivasan, S.; Wheeler, M.

    2016-12-01

    Optimal management of subsurface processes requires the characterization of the uncertainty in reservoir description and reservoir performance prediction. For fractured reservoirs, the location and orientation of fractures is crucial for predicting production characteristics. With the help of accurate and comprehensive knowledge of fracture distributions, early water / CO2 breakthrough can be prevented and sweep efficiency can be improved. However, since the rock property fields are highly non-Gaussian in this case, it is a challenge to estimate fracture distributions by conventional history matching approaches. In this work, a method that combines vector-based level-set parameterization technique and ensemble Kalman filter (EnKF) for estimating fracture distributions is presented. On the other hand, modeling fluid flow through fracture networks is challenging due to the geometric characteristics of fractures. In addition, the context of uncertainty quantification adds further challenges. Correctly sampling random realizations requires a fast and robust mesh representation and forward modeling. Our approach has been to circumvent traditional mesh generation by using methods that allow for general polyhedral elements. A discrete fracture model based on the Mimetic Finite Difference (MFD) method is utilized as forward modeling. In this research, we integrate mesh generation, MFD forward modeling, EnKF with parameterization in an automatic workflow. By applying this workflow on two-dimensional two-phase fractured reservoirs examples, it demonstrates that our proposed workflow provides an effective solution to address the challenges in the history matching problem of highly non-Gaussian fractured reservoirs.

  1. The Sea as a Rich Source of Structurally Unique Glycosaminoglycans and Mimetics

    PubMed Central

    Vasconcelos, Ariana A.; Pomin, Vitor H.

    2017-01-01

    Glycosaminoglycans (GAGs) are sulfated glycans capable of regulating various biological and medical functions. Heparin, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate and hyaluronan are the principal classes of GAGs found in animals. Although GAGs are all composed of disaccharide repeating building blocks, the sulfation patterns and the composing alternating monosaccharides vary among classes. Interestingly, GAGs from marine organisms can present structures clearly distinct from terrestrial animals even considering the same class of GAG. The holothurian fucosylated chondroitin sulfate, the dermatan sulfates with distinct sulfation patterns extracted from ascidian species, the sulfated glucuronic acid-containing heparan sulfate isolated from the gastropode Nodipecten nodosum, and the hybrid heparin/heparan sulfate molecule obtained from the shrimp Litopenaeus vannamei are some typical examples. Besides being a rich source of structurally unique GAGs, the sea is also a wealthy environment of GAG-resembling sulfated glycans. Examples of these mimetics are the sulfated fucans and sulfated galactans found in brown, red and green algae, sea urchins and sea cucumbers. For adequate visualization, representations of all discussed molecules are given in both Haworth projections and 3D models. PMID:28846656

  2. Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling

    PubMed Central

    Kushal, Swati; Lao, Brooke Bullock; Henchey, Laura K.; Dubey, Ramin; Mesallati, Hanah; Traaseth, Nathaniel J.; Olenyuk, Bogdan Z.; Arora, Paramjit S.

    2013-01-01

    Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. Herein we report the design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor hypoxia-inducible factor-1α. Our results indicate that disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of nontargeted signaling pathways. We observed remarkable efficacy of the compound HBS 1 in suppressing tumor growth in the fully established murine xenograft models of renal cell carcinoma of the clear cell type. Our results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor–coactivator interfaces represent a unique approach for in vivo modulation of oncogenic signaling and arresting tumor growth. PMID:24019500

  3. Protein domain mimetics as in vivo modulators of hypoxia-inducible factor signaling.

    PubMed

    Kushal, Swati; Lao, Brooke Bullock; Henchey, Laura K; Dubey, Ramin; Mesallati, Hanah; Traaseth, Nathaniel J; Olenyuk, Bogdan Z; Arora, Paramjit S

    2013-09-24

    Selective blockade of gene expression by designed small molecules is a fundamental challenge at the interface of chemistry, biology, and medicine. Transcription factors have been among the most elusive targets in genetics and drug discovery, but the fields of chemical biology and genetics have evolved to a point where this task can be addressed. Herein we report the design, synthesis, and in vivo efficacy evaluation of a protein domain mimetic targeting the interaction of the p300/CBP coactivator with the transcription factor hypoxia-inducible factor-1α. Our results indicate that disrupting this interaction results in a rapid down-regulation of hypoxia-inducible genes critical for cancer progression. The observed effects were compound-specific and dose-dependent. Gene expression profiling with oligonucleotide microarrays revealed effective inhibition of hypoxia-inducible genes with relatively minimal perturbation of nontargeted signaling pathways. We observed remarkable efficacy of the compound HBS 1 in suppressing tumor growth in the fully established murine xenograft models of renal cell carcinoma of the clear cell type. Our results suggest that rationally designed synthetic mimics of protein subdomains that target the transcription factor-coactivator interfaces represent a unique approach for in vivo modulation of oncogenic signaling and arresting tumor growth.

  4. Nanoscale engineering of extracellular matrix-mimetic bioadhesive surfaces and implants for tissue engineering.

    PubMed

    Shekaran, Asha; Garcia, Andres J

    2011-03-01

    The goal of tissue engineering is to restore tissue function using biomimetic scaffolds which direct desired cell fates such as attachment, proliferation and differentiation. Cell behavior in vivo is determined by a complex interaction of cells with extracellular biosignals, many of which exist on a nanoscale. Therefore, recent efforts in tissue engineering biomaterial development have focused on incorporating extracellular matrix- (ECM) derived peptides or proteins into biomaterials in order to mimic natural ECM. Concurrent advances in nanotechnology have also made it possible to manipulate protein and peptide presentation on surfaces on a nanoscale level. This review discusses protein and peptide nanopatterning techniques and examples of how nanoscale engineering of bioadhesive materials may enhance outcomes for regenerative medicine. Synergy between ECM-mimetic tissue engineering and nanotechnology fields can be found in three major strategies: (1) Mimicking nanoscale orientation of ECM peptide domains to maintain native bioactivity, (2) Presenting adhesive peptides at unnaturally high densities, and (3) Engineering multivalent ECM-derived peptide constructs. Combining bioadhesion and nanopatterning technologies to allow nanoscale control of adhesive motifs on the cell-material interface may result in exciting advances in tissue engineering. This article is part of a Special Issue entitled Nanotechnologies - Emerging Applications in Biomedicine. 2010 Elsevier B.V. All rights reserved.

  5. Mussel-mimetic tissue adhesive for fetal membrane repair: an ex vivo evaluation.

    PubMed

    Haller, C M; Buerzle, W; Kivelio, A; Perrini, M; Brubaker, C E; Gubeli, R J; Mallik, A S; Weber, W; Messersmith, P B; Mazza, E; Ochsenbein-Koelble, N; Zimmermann, R; Ehrbar, M

    2012-12-01

    Iatrogenic preterm prelabor rupture of membranes (iPPROM) remains the main complication after invasive interventions into the intrauterine cavity. Here, the proteolytic stability of mussel-mimetic tissue adhesive (mussel glue) and its sealing behavior on punctured fetal membranes are evaluated. The proteolytic degradation of mussel glue and fibrin glue were compared in vitro. Critical pressures of punctured and sealed fetal membranes were determined under close to physiological conditions using a custom-made inflation device. An inverse finite element procedure was applied to estimate mechanical parameters of mussel glue. Mussel glue was insensitive whereas fibrin glue was sensitive towards proteolytic degradation. Mussel glue sealed 3.7mm fetal membrane defect up to 60mbar (45mmHg) when applied under wet conditions, whereas fibrin glue needed dry membrane surfaces for reliable sealing. The mussel glue can be represented by a neo-Hookean material model with elastic coefficient C(1)=9.63kPa. Ex-vivo-tested mussel glue sealed fetal membranes and resisted pressures achieved during uterine contractions. Together with good stability in proteolytic environments, this makes mussel glue a promising sealing material for future applications. Copyright © 2012 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  6. Inhibition of human amylin fibril formation by insulin-mimetic vanadium complexes.

    PubMed

    He, Lei; Wang, Xuesong; Zhao, Cong; Zhu, Dengsen; Du, Weihong

    2014-05-01

    The toxicity of amyloid-forming proteins can be linked to many degenerative and systemic diseases. Human islet amyloid polypeptide (hIAPP, amylin) has been associated with type II diabetes. Methods for efficient inhibition of amyloid fibril formation are highly clinically important. This study demonstrated the significant inhibitory effects of six vanadium complexes on hIAPP aggregation. Vanadium complexes, such as bis(maltolato)-oxovanadium (BMOV), have been used as insulin-mimetic agents for the treatment of diabetes for many years. Different biophysical methods were applied to investigate the interaction between V complexes and hIAPP. The results indicated that the selected compounds affected the peptide aggregation by different action modes and protected the cells from the cytotoxicity induced by hIAPP. Both the high binding affinity and the ligand spatial effect on inhibiting hIAPP aggregation are significant. Although some of these compounds undergo biotransformation under the conditions of the experiments, and the active species are not identified, it is understood that the effect results from a particular compound and its conversion products. Importantly, our work provided information on the effects of the selected V complexes on hIAPP and demonstrated multiple levels of effects of V complexes against amyloid-related diseases.

  7. Population genomics of parallel hybrid zones in the mimetic butterflies, H. melpomene and H. erato

    PubMed Central

    Ruiz, Mayté; Salazar, Patricio; Counterman, Brian; Medina, Jose Alejandro; Ortiz-Zuazaga, Humberto; Morrison, Anna; Papa, Riccardo

    2014-01-01

    Hybrid zones can be valuable tools for studying evolution and identifying genomic regions responsible for adaptive divergence and underlying phenotypic variation. Hybrid zones between subspecies of Heliconius butterflies can be very narrow and are maintained by strong selection acting on color pattern. The comimetic species, H. erato and H. melpomene, have parallel hybrid zones in which both species undergo a change from one color pattern form to another. We use restriction-associated DNA sequencing to obtain several thousand genome-wide sequence markers and use these to analyze patterns of population divergence across two pairs of parallel hybrid zones in Peru and Ecuador. We compare two approaches for analysis of this type of data—alignment to a reference genome and de novo assembly—and find that alignment gives the best results for species both closely (H. melpomene) and distantly (H. erato, ∼15% divergent) related to the reference sequence. Our results confirm that the color pattern controlling loci account for the majority of divergent regions across the genome, but we also detect other divergent regions apparently unlinked to color pattern differences. We also use association mapping to identify previously unmapped color pattern loci, in particular the Ro locus. Finally, we identify a new cryptic population of H. timareta in Ecuador, which occurs at relatively low altitude and is mimetic with H. melpomene malleti. PMID:24823669

  8. Defensive Chemistry of Lycid Beetles and of Mimetic Cerambycid Beetles that Feed on Them

    PubMed Central

    Eisner, Thomas; Schroeder, Frank C.; Snyder, Noel; Grant, Jacqualine B.; Aneshansley, Daniel J.; Utterback, David; Meinwald, Jerrold; Eisner, Maria

    2008-01-01

    Summary Beetles of the family Lycidae have long been known to be chemically protected. We present evidence that North American species of the lycid genera Calopteron and Lycus are rejected by thrushes, wolf spiders, and orb-weaving spiders, and that they contain a systemic compound that could account, at least in part, for this unacceptability. This compound, a novel acetylenic acid that we named lycidic acid, proved actively deterrent in feeding tests with wolf spiders and coccinellid beetles. Species of Lycus commonly figure as models of mimetic associations. Among their mimics are species of the cerambycid beetle genus Elytroleptus, remarkable because they prey upon the model lycids. We postulated that by doing so Elytroleptus might incorporate the lycidic acid from their prey for their own defense. However, judging from analytical data, the beetles practice no such sequestration, explaining why they remain relatively palatable (in tests with wolf spiders) even after having fed on lycids. Chemical analyses also showed the lycids to contain pyrazines, such as were already known from other Lycidae, potent odorants that could serve in an aposematic capacity to forestall predatory attacks. PMID:18698369

  9. Design and facile synthesis of neoglycolipids as lactosylceramide mimetics and their transformation into glycoliposomes.

    PubMed

    Harada, Yoichiro; Murata, Takeomi; Totani, Kazuhide; Kajimoto, Tetsuya; Masum, Shah Md; Tamba, Yukihiro; Yamazaki, Masahito; Usui, Taichi

    2005-01-01

    Neoglycolipids composed of disaccharide glycoside and phospholipid were designed and prepared as mimetics of lactosylceramide. The lactosyl- and N-acetyllactosaminyl-phospholipids (Lac-DPPA and LacNAc-DPPA) were enzymatically synthesized from lactose and LacNAc respectively by cellulase-mediated condensation with 1,6-hexanediol, followed by conjugation of the resulting glycosides and dipalmitoylphosphatidyl choline (DPPC) mediated by Streptomyces phospholipase D. Alternatively, allyl beta-lactoside was ozonolyzed to give an aldehyde, which was condensed with dipalmytoyl phosphatidyl ethanolamine to afford a second type of glycolipid (Lac-DPPE). NMR spectroscopy indicated that the neoglycolipids behave differently in different solvent systems. X-ray diffraction clearly showed that multilamellar vesicles (MLVs) of Lac-DPPE and Lac-DPPA-MLV are in the bilayer gel phase at 20 degrees C, whereas those of Lac-DPPE-MLV were in the lamellar liquid-crystalline phase at 50 degrees C. Differential scanning calorimetry showed that Lac-DPPE-MLV had complex thermotropic behavior depending on the incubation conditions. After a long incubation at 10 degrees C, endothermic transitions are observed at 39.6, 42.3 degrees C, and 42.9 degrees C. These neoglycolipids have the ability to trap calcein, a chelating derivative of fluorescein, in MLVs and showed specific binding to lectin in plate assays using fluorescently labeled compounds.

  10. Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy.

    PubMed

    Alvarez, Rafael; Casas, Jesús; López, David J; Ibarguren, Maitane; Suari-Rivera, Ariadna; Terés, Silvia; Guardiola-Serrano, Francisca; Lossos, Alexander; Busquets, Xavier; Kakhlon, Or; Escribá, Pablo V

    2017-08-01

    Adult polyglucosan body disease (APBD) is a neurological disorder characterized by adult-onset neurogenic bladder, spasticity, weakness, and sensory loss. The disease is caused by aberrant glycogen branching enzyme (GBE) (GBE1Y329S) yielding less branched, globular, and soluble glycogen, which tends to aggregate. We explore here whether, despite being a soluble enzyme, GBE1 activity is regulated by protein-membrane interactions. Because soluble proteins can contact a wide variety of cell membranes, we investigated the interactions of purified WT and GBE1Y329S proteins with different types of model membranes (liposomes). Interestingly, both triheptanoin and some triacylglycerol mimetics (TGMs) we have designed (TGM0 and TGM5) markedly enhance GBE1Y329S activity, possibly enough for reversing APBD symptoms. We show that the GBE1Y329S mutation exposes a hydrophobic amino acid stretch, which can either stabilize and enhance or alternatively, reduce the enzyme activity via alteration of protein-membrane interactions. Additionally, we found that WT, but not Y329S, GBE1 activity is modulated by Ca 2+ and phosphatidylserine, probably associated with GBE1-mediated regulation of energy consumption and storage. The thermal stabilization and increase in GBE1Y329S activity induced by TGM5 and its omega-3 oil structure suggest that this molecule has a considerable therapeutic potential for treating APBD. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  11. Activity of Antimicrobial Peptide Mimetics in the Oral Cavity: I. Activity Against Biofilms of Candida albicans

    PubMed Central

    Hua, Jianyuan; Yamarthy, Radha; Felsenstein, Shaina; Scott, Richard W.; Markowitz, Kenneth; Diamond, Gill

    2010-01-01

    Summary Naturally occurring antimicrobial peptides hold promise as therapeutic agents against oral pathogens such as Candida albicans, however numerous difficulties have slowed their development. Synthetic, non-peptidic analogs that mimic the properties of these peptides have many advantages and exhibit potent, selective antimicrobial activity. Several series of mimetics (MW <1,000) were developed and screened against oral Candida strains as a proof-of-principle for their antifungal properties. One phenylalkyne and several arylamide compounds with reduced mammalian cytotoxicities were found to be active against C. albicans. These compounds demonstrated rapid fungicidal activity in liquid culture even in the presence of saliva, and demonstrated synergy with standard antifungal agents. When assayed against biofilms grown on denture acrylic, the compounds exhibited potent fungicidal activity as measured by metabolic and fluorescent viability assays. Repeated passages in sub-MIC levels did not lead to resistant Candida in contrast to fluconazole. Our results demonstrate the proof-of principle for the use of these compounds as anti-Candida agents, and their further testing is warranted as novel anti-Candida therapies. PMID:21040515

  12. Transthyretin Mimetics as Anti-β-Amyloid Agents: A Comparison of Peptide and Protein Approaches.

    PubMed

    Pate, Kayla M; Kim, Brandon J; Shusta, Eric V; Murphy, Regina M

    2018-03-07

    β-Amyloid (Aβ) aggregation is causally linked to neuronal pathology in Alzheimer's disease; therefore, several small molecules, antibodies, and peptides have been tested as anti-Aβ agents. We developed two compounds based on the Aβ-binding domain of transthyretin (TTR): a cyclic peptide cG8 and an engineered protein mTTR, and compared them for therapeutically relevant properties. Both mTTR and cG8 inhibit fibrillogenesis of Aβ, with mTTR inhibiting at a lower concentration than cG8. Both inhibit aggregation of amylin but not of α-synuclein. They both bind more Aβ aggregates than monomer, and neither disaggregates preformed fibrils. cG8 retained more of its activity in the presence of biological materials and was more resistant to proteolysis than mTTR. We examined the effect of mTTR or cG8 on Aβ binding to human neurons. When mTTR was co-incubated with Aβ under oligomer-forming conditions, Aβ morphology was drastically changed and Aβ-cell deposition significantly decreased. In contrast, cG8 did not affect morphology but decreased the amount of Aβ deposited. These results provide guidance for further evolution of TTR-mimetic anti-amyloid agents. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  13. Defensive Chemistry of Lycid Beetles and of Mimetic Cerambycid Beetles that Feed on Them.

    PubMed

    Eisner, Thomas; Schroeder, Frank C; Snyder, Noel; Grant, Jacqualine B; Aneshansley, Daniel J; Utterback, David; Meinwald, Jerrold; Eisner, Maria

    2008-01-01

    Beetles of the family Lycidae have long been known to be chemically protected. We present evidence that North American species of the lycid genera Calopteron and Lycus are rejected by thrushes, wolf spiders, and orb-weaving spiders, and that they contain a systemic compound that could account, at least in part, for this unacceptability. This compound, a novel acetylenic acid that we named lycidic acid, proved actively deterrent in feeding tests with wolf spiders and coccinellid beetles.Species of Lycus commonly figure as models of mimetic associations. Among their mimics are species of the cerambycid beetle genus Elytroleptus, remarkable because they prey upon the model lycids. We postulated that by doing so Elytroleptus might incorporate the lycidic acid from their prey for their own defense. However, judging from analytical data, the beetles practice no such sequestration, explaining why they remain relatively palatable (in tests with wolf spiders) even after having fed on lycids. Chemical analyses also showed the lycids to contain pyrazines, such as were already known from other Lycidae, potent odorants that could serve in an aposematic capacity to forestall predatory attacks.

  14. Structurally Ordered Nanowire Formation from Co-Assembly of DNA Origami and Collagen-Mimetic Peptides

    SciTech Connect

    Jiang, Tao; Meyer, Travis A.; Modlin, Charles

    2017-10-02

    We describe the co-assembly of two different building units: collagen-mimetic peptides and DNA origami. Two peptides CP++ and sCP(++) are designed with a sequence comprising a central block (Pro-Hyp-Gly) and two positively charged domains (Pro-Arg-Gly) at both N- and C-termini. Co-assembly of peptides and DNA origami two-layer (TL) nanosheets affords the formation of one-dimensional nanowires with repeating periodicity of similar to 10 nm. Structural analyses suggest a face-to-face stacking of DNA nanosheets with peptides aligned perpendicularly to the sheet surfaces. We demonstrate the potential of selective peptide-DNA association between face-to-face and edge-to-edge packing by tailoring the size of DNA nanostructures.more » This study presents an attractive strategy to create hybrid biomolecular assemblies from peptide and DNA-based building blocks that takes advantage of the intrinsic chemical and physical properties of the respective components to encode structural and, potentially, functional complexity within readily accessible biomimetic materials.« less

  15. Discrete conservation properties for shallow water flows using mixed mimetic spectral elements

    NASA Astrophysics Data System (ADS)

    Lee, D.; Palha, A.; Gerritsma, M.

    2018-03-01

    A mixed mimetic spectral element method is applied to solve the rotating shallow water equations. The mixed method uses the recently developed spectral element histopolation functions, which exactly satisfy the fundamental theorem of calculus with respect to the standard Lagrange basis functions in one dimension. These are used to construct tensor product solution spaces which satisfy the generalized Stokes theorem, as well as the annihilation of the gradient operator by the curl and the curl by the divergence. This allows for the exact conservation of first order moments (mass, vorticity), as well as higher moments (energy, potential enstrophy), subject to the truncation error of the time stepping scheme. The continuity equation is solved in the strong form, such that mass conservation holds point wise, while the momentum equation is solved in the weak form such that vorticity is globally conserved. While mass, vorticity and energy conservation hold for any quadrature rule, potential enstrophy conservation is dependent on exact spatial integration. The method possesses a weak form statement of geostrophic balance due to the compatible nature of the solution spaces and arbitrarily high order spatial error convergence.

  16. Synthetic mimetics of the endogenous gastrointestinal nanomineral: Silent constructs that trap macromolecules for intracellular delivery.

    PubMed

    Pele, Laetitia C; Haas, Carolin T; Hewitt, Rachel E; Robertson, Jack; Skepper, Jeremy; Brown, Andy; Hernandez-Garrido, Juan Carlos; Midgley, Paul A; Faria, Nuno; Chappell, Helen; Powell, Jonathan J

    2017-02-01

    Amorphous magnesium-substituted calcium phosphate (AMCP) nanoparticles (75-150nm) form constitutively in large numbers in the mammalian gut. Collective evidence indicates that they trap and deliver luminal macromolecules to mucosal antigen presenting cells (APCs) and facilitate gut immune homeostasis. Here, we report on a synthetic mimetic of the endogenous AMCP and show that it has marked capacity to trap macromolecules during formation. Macromolecular capture into AMCP involved incorporation as shown by STEM tomography of the synthetic AMCP particle with 5nm ultra-fine iron (III) oxohydroxide. In vitro, organic cargo-loaded synthetic AMCP was taken up by APCs and tracked to lysosomal compartments. The AMCP itself did not regulate any gene, or modify any gene regulation by its cargo, based upon whole genome transcriptomic analyses. We conclude that synthetic AMCP can efficiently trap macromolecules and deliver them to APCs in a silent fashion, and may thus represent a new platform for antigen delivery. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

  17. Inhibition of Blood-Brain Barrier Disruption by an Apolipoprotein E-Mimetic Peptide Ameliorates Early Brain Injury in Experimental Subarachnoid Hemorrhage.

    PubMed

    Pang, Jinwei; Chen, Yitian; Kuai, Li; Yang, Ping; Peng, Jianhua; Wu, Yue; Chen, Yue; Vitek, Michael P; Chen, Ligang; Sun, Xiaochuan; Jiang, Yong

    2017-06-01

    Apolipoprotein E (ApoE)-mimetic peptides have been demonstrated to be beneficial in secondary brain injury following experimental subarachnoid hemorrhage (SAH). However, the molecular mechanisms underlying these benefits in SAH models have not been clearly identified. This study investigated whether an ApoE-mimetic peptide affords neuroprotection in early brain injury (EBI) following SAH by attenuating BBB disruption. SAH was induced by an endovascular perforation in young, healthy, male wild-type (WT) C57BL/6J mice. Multiple techniques, including MRI with T2-weighted imaging, 18 FDG PET-CT scanning and histological studies, were used to examine BBB integrity and neurological dysfunction in EBI following SAH. We found that SAH induced a significant increase of BBB permeability and neuron apoptosis, whereas ApoE-mimetic peptide treatment significantly reduced the degradation of tight junction proteins and endothelial cell apoptosis. These effects reduced brain edema and neuron apoptosis, increased cerebral glucose uptake, and improved neurological functions. Further investigation revealed that the ApoE-mimetic peptide inhibited the proinflammatory activators of MMP-9, including CypA, NF-κB, IL-6, TNF-α, and IL-1β, thereby ameliorating BBB disruption at the acute stage of SAH. Together, these data indicate that ApoE-mimetic peptide may be a novel and promising therapeutic strategy for EBI amelioration after SAH that are worthy of further study.

  18. Design and synthesis of collagen mimetic peptide derivatives for studying triple helix assembly and collagen mimetic peptide-collagen binding interaction

    NASA Astrophysics Data System (ADS)

    Mo, Xiao

    2008-10-01

    Collagen is the principal tensile clement of the extra-cellular matrix in mammals and is the basic scaffold for cells and tissues. Collagen molecules are comprised of homo-trimeric helices (e.g. collagen type II and type III), ABB type hetero-trimeric helices (e.g. collagen type I, type IV, and type V), or ABC type hetero-trimeric helices (e.g. type V). Mimicry of collagen structures can help elucidate collagen triple helical conformation and provide insights into making novel collagen-like biomaterials. Our group previously reported a new physical collagen modification method, which was based on non-covalent interaction between collagen mimetic peptide (CMP: -(Pro-Hyp-Gly) x-) and natural collagen. We hypothesized that CMP binds to collagen through a process involving both strand invasion and triple helix assembly. The aim of this dissertation is to study structural formation and stability of collagen triple helix, and to investigate CMP-collagen binding interactions using two types of CMP derivatives: covalently templated CMP trimer and CMP-nanoparticle conjugates. We demonstrated that covalently templated ABB type CMP hetero-trimers could be prepared by a versatile synthetic strategy involving both solid phase and solution peptide coupling. Our thermal melting studies showed that the templated CMP hetero-trimers formed collagen-like triple helices and their folding kinetics correlated with the amino acid compositions of the individual CMP strands. We also studied the thermal melting behavior and folding kinetics of a templated hetero-trimer complex comprised of CMP and a peptide derived from collagen. This synthetic strategy can be readily extended to synthesize other ABB type hetero-trimers to investigate their local melting behavior and biological activity. We also prepared colloidally stable CMP functionalized gold nanoparticles (Au-CMPs) as a TEM marker for investigating the CMP-collagen interaction. Au-CMP showed preferential binding to collagen fiber's gap

  19. An investigation of the mimetic enzyme activity of two-dimensional Pd-based nanostructures

    NASA Astrophysics Data System (ADS)

    Wei, Jingping; Chen, Xiaolan; Shi, Saige; Mo, Shiguang; Zheng, Nanfeng

    2015-11-01

    In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis.In this work, we investigated the mimetic enzyme activity of two-dimensional (2D) Pd-based nanostructures (e.g. Pd nanosheets, Pd@Au and Pd@Pt nanoplates) and found that they possess intrinsic peroxidase-, oxidase- and catalase-like activities. These nanostructures were able to activate hydrogen peroxide or dissolved oxygen for catalyzing the oxidation of organic substrates, and decompose hydrogen peroxide to generate oxygen. More systematic investigations revealed that the peroxidase-like activities of these Pd-based nanomaterials were highly structure- and composition-dependent. Among them, Pd@Pt nanoplates displayed the highest peroxidase-like activity. Based on these findings, Pd-based nanostructures were applied for the colorimetric detection of H2O2 and glucose, and also the electro-catalytic reduction of H2O2. This work offers a promising prospect for the application of 2D noble metal nanostructures in biocatalysis. Electronic supplementary information (ESI) available: TEM images, EDX and dispersion stability of Pd-based nanomaterials

  20. Mussel mimetic tissue adhesive for fetal membrane repair: initial in vivo investigation in rabbits.

    PubMed

    Kivelio, A; Dekoninck, P; Perrini, M; Brubaker, C E; Messersmith, P B; Mazza, E; Deprest, J; Zimmermann, R; Ehrbar, M; Ochsenbein-Koelble, N

    2013-12-01

    Iatrogenic preterm prelabour rupture of fetal membranes (iPPROM) remains the main complication after invasive interventions into the intrauterine cavity. The aim of this study was to evaluate the sealing capability and tissue interaction of mussel-mimetic tissue adhesive (mussel glue) in comparison to fibrin glue on punctured fetal membranes in vivo. A mid-gestational rabbit model was used for testing the materials. The fetal sacs of pregnant rabbits at day 23 were randomly assigned into experimental groups: unoperated (negative control), unclosed puncture (positive control), commercially available fibrin glue (FG) with decellularized amnion scaffold (DAM), mussel glue (MG) with DAM, or mussel glue alone. Evaluation was done at term (30 days' gestation) assessing fetal survival, fetal membrane integrity and histology of the membranes. Fetal survival was not significantly lower in any of the treatment groups compared to the negative control. All plugging materials could be found at the end of the pregnancy and no adverse effects on the fetus or the pregnant does could be observed. Sac integrity was higher in all treatment groups compared to the positive control group but significant only in the FG+DAM group. Cellular infiltration could be seen in fibrin glue and DAM in contrast to mussel glue which was only tightly adhering to the surrounding tissue. These cells were mostly of mesenchymal phenotype staining positive for vimentin. CD68 positive macrophages were found clustered around all the plugging materials, but their numbers were only significantly increased for the mussel glue alone group compared to negative controls. Mussel glues performance in sealing fetal membranes in the rabbit model was comparable to that of fibrin glue. Taking into account its other favorable properties, it is a noteworthy candidate for a clinically applicable fetal membrane sealant. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  1. Perylene Diimide as a Precise Graphene-like Superoxide Dismutase Mimetic

    SciTech Connect

    Jalilov, Almaz S.; Nilewski, Lizanne G.; Berka, Vladimir

    2017-01-31

    Here we show that the active portion of a graphitic nanoparticle can be mimicked by a perylene diimide (PDI) to explain the otherwise elusive biological and electrocatalytic activity of the nanoparticle construct. Development of molecular analogues that mimic the antioxidant properties of oxidized graphenes, in this case the poly(ethylene glycolated) hydrophilic carbon clusters (PEG–HCCs), will afford important insights into the highly efficient activity of PEG–HCCs and their graphitic analogues. PEGylated perylene diimides (PEGn–PDI) serve as well-defined molecular analogues of PEG–HCCs and oxidized graphenes in general, and their antioxidant and superoxide dismutase-like (SOD-like) properties were studied. PEGn–PDIs have two reversible reductionmore » peaks, which are more positive than the oxidation peak of superoxide (O2•–). This is similar to the reduction peak of the HCCs. Thus, as with PEG–HCCs, PEGn–PDIs are also strong single-electron oxidants of O2•–. Furthermore, reduced PEGn–PDI, PEGn–PDI•–, in the presence of protons, was shown to reduce O2•– to H2O2 to complete the catalytic cycle in this SOD analogue. The kinetics of the conversion of O2•– to O2 and H2O2 by PEG8–PDI was measured using freeze-trap EPR experiments to provide a turnover number of 133 s–1; the similarity in kinetics further supports that PEG8–PDI is a true SOD mimetic. Finally, PDIs can be used as catalysts in the electrochemical oxygen reduction reaction in water, which proceeds by a two-electron process with the production of H2O2, mimicking graphene oxide nanoparticles that are otherwise difficult to study spectroscopically.« less

  2. An Independent Evaluation of a Novel Peptide Mimetic, Brilacidin (PMX30063), for Ocular Anti-Infective

    PubMed Central

    Romanowski, Eric G.; Yates, Kathleen A.; Mah, Francis S.

    2016-01-01

    Abstract Purpose: Brilacidin (BRI), a novel defensin mimetic, was evaluated as an ocular anti-infective. Methods: In vitro: Potency based on MIC90s was compared for 50 Staphylococcus aureus (SA), 50 Staphylococcus epidermidis (SE), and 25 each of Streptococcus pneumonia (SP), Streptococcus viridans (SV), Moraxella (MS), Haemophilus influenzae (HI), Pseudomonas aeruginosa (PA), and Serratia marcescens (SM). In vivo: Using established methods, ocular toxicity was graded with Draize testing. For efficacy testing, both corneas of 24 rabbits were infected with methicillin-resistant S. aureus (MRSA), whereas the corneal epithelium was removed in the left eye. After 4 h, 21 topical drops over 5 h were administered to 4 groups: BRI 0.5%, vancomycin (VAN) 5%, saline, and no treatment. The eyes were clinically graded and the corneas were harvested for colony counts. Results: In vitro: Both SA and SE had the lowest minimum inhibitory concentrations among the bacterial groups. The MIC90s to BRI for SP, SV, MS, HI, PA, and SM were 4, 32, 256, 32, 16, and 128-fold higher, respectively, than SA and SE. In vivo: Draize testing determined BRI 0.5% to be minimally irritating. For abraded corneas, BRI was not statistically different from VAN for reducing MRSA. BRI was bactericidal. For intact corneas, VAN reduced more CFU than BRI. BRI reduced CFU in abraded corneas more than intact corneas suggesting poor corneal penetration. Conclusions: BRI has Gram-positive in vitro activity; topical BRI 0.5% was minimally irritating; and BRI 0.5% was equally efficacious as VAN in a MRSA keratitis model when the corneal epithelium was removed. PMID:26501484

  3. Dramatic nano-fluidic properties of carbon nanotube membranes as a platform for protein channel mimetics

    NASA Astrophysics Data System (ADS)

    Hinds, Bruce

    2013-03-01

    Carbon nanotubes have three key attributes that make them of great interest for novel membrane applications: 1) atomically flat graphite surface allows for ideal fluid slip boundary conditions and extremely fast flow rates 2) the cutting process to open CNTs inherently places functional chemistry at CNT core entrance for chemical selectivity and 3) CNT are electrically conductive allowing for electrochemical reactions and application of electric fields gradients at CNT tips. Pressure driven flux of a variety of solvents (H2O, hexane, decane ethanol, methanol) are 4-5 orders of magnitude higher than conventional Newtonian flow [Nature 2005, 438, 44] due to atomically flat graphite planes inducing nearly ideal slip conditions. However this is eliminated with selective chemical functionalization [ACS Nano 2011 5(5) 3867-3877] needed to give chemical selectivity. These unique properties allow us to explore the hypothesis of producing ``Gatekeeper'' membranes that mimic natural protein channels to actively pump through rapid nm-scale channels. With anionic tip functionality strong electroosmotic flow is induced by unimpeded cation flow with similar 10,000 fold enhancements [Nature Nano 2012 7(2) 133-39]. With enhanced power efficiency, carbon nanotube membranes were employed as the active element of a switchable transdermal drug delivery device that can facilitate more effective treatments of drug abuse and addiction. Recently methods to deposit Pt monolayers on CNT surface have been developed making for highly efficient catalytic platforms. Discussed are other applications of CNT protein channel mimetics, for large area robust engineering platforms, including water purification, flow battery energy storage, and biochemical/biomass separations. DOE EPSCoR (DE-FG02-07ER46375) and DARPA, W911NF-09-1-0267

  4. Three-dimensional elastomeric scaffolds designed with cardiac-mimetic structural and mechanical features.

    PubMed

    Neal, Rebekah A; Jean, Aurélie; Park, Hyoungshin; Wu, Patrick B; Hsiao, James; Engelmayr, George C; Langer, Robert; Freed, Lisa E

    2013-03-01

    Tissue-engineered constructs, at the interface of material science, biology, engineering, and medicine, have the capacity to improve outcomes for cardiac patients by providing living cells and degradable biomaterials that can regenerate the native myocardium. With an ultimate goal of both delivering cells and providing mechanical support to the healing heart, we designed three-dimensional (3D) elastomeric scaffolds with (1) stiffnesses and anisotropy mimicking explanted myocardial specimens as predicted by finite-element (FE) modeling, (2) systematically varied combinations of rectangular pore pattern, pore aspect ratio, and strut width, and (3) structural features approaching tissue scale. Based on predicted mechanical properties, three scaffold designs were selected from eight candidates for fabrication from poly(glycerol sebacate) by micromolding from silicon wafers. Large 20×20 mm scaffolds with high aspect ratio features (5:1 strut height:strut width) were reproducibly cast, cured, and demolded at a relatively high throughput. Empirically measured mechanical properties demonstrated that scaffolds were cardiac mimetic and validated FE model predictions. Two-layered scaffolds providing fully interconnected pore networks were fabricated by layer-by-layer assembly. C2C12 myoblasts cultured on one-layered scaffolds exhibited specific patterns of cell elongation and interconnectivity that appeared to be guided by the scaffold pore pattern. Neonatal rat heart cells cultured on two-layered scaffolds for 1 week were contractile, both spontaneously and in response to electrical stimulation, and expressed sarcomeric α-actinin, a cardiac biomarker. This work not only demonstrated several scaffold designs that promoted functional assembly of rat heart cells, but also provided the foundation for further computational and empirical investigations of 3D elastomeric scaffolds for cardiac tissue engineering.

  5. Smac mimetic sensitizes renal cell carcinoma cells to interferon-α-induced apoptosis.

    PubMed

    Reiter, Michael; Eckhardt, Ines; Haferkamp, Axel; Fulda, Simone

    2016-05-28

    The prognosis of metastatic or relapsed renal cell carcinoma (RCC) is still very poor, highlighting the need for new treatment strategies. Here, we identify a cooperative antitumor activity of interferon-α (IFNα) together with the Smac mimetic BV6 that antagonizes antiapoptotic IAP proteins. BV6 and IFNα act together to reduce cell viability and to induce apoptosis in various RCC cell lines. Molecular studies revealed that BV6/IFNα co-treatment triggers apoptosis independently of autocrine/paracrine Tumor Necrosis Factor (TNF)α signaling, since the TNFα-blocking antibody Enbrel fails to rescue cell death. Importantly, knockdown of Receptor-Interacting Protein (RIP)1 significantly decreases BV6/IFNα-mediated apoptosis, whereas the RIP1 kinase inhibitor necrostatin-1 (Nec-1) provides no protection. This demonstrates that RIP1 protein is critically required for BV6/IFNα-induced apoptosis, while RIP1 kinase activity is dispensable, pointing to a scaffold function of RIP1. Consistently, BV6 and IFNα cooperate to trigger the interaction of RIP1, Fas-Associated Death Domain protein (FADD) and caspase-8 to form a cytosolic cell death complex that drives caspase activation. Addition of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly protects RCC cells against BV6/IFNα-induced apoptosis, demonstrating that caspase activity is required for apoptosis. In conclusion, the combination approach of IFNα and BV6 represents a promising strategy for cooperative induction of apoptosis in RCC cells, which warrants further investigation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  6. Stable Incretin Mimetics Counter Rapid Deterioration of Bone Quality in Type 1 Diabetes Mellitus.

    PubMed

    Mansur, Sity Aishah; Mieczkowska, Aleksandra; Bouvard, Béatrice; Flatt, Peter R; Chappard, Daniel; Irwin, Nigel; Mabilleau, Guillaume

    2015-12-01

    Type 1 diabetes mellitus is associated with a high risk for bone fractures. Although bone mass is reduced, bone quality is also dramatically altered in this disorder. However, recent evidences suggest a beneficial effect of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) pathways on bone quality. The aims of the present study were to conduct a comprehensive investigation of bone strength at the organ and tissue level; and to ascertain whether enzyme resistant GIP or GLP-1 mimetic could be beneficial in preventing bone fragility in type 1 diabetes mellitus. Streptozotocin-treated mice were used as a model of type 1 diabetes mellitus. Control and streptozotocin-diabetic animals were treated for 21 days with an enzymatic-resistant GIP peptide ([D-Ala(2) ]GIP) or with liraglutide (each at 25 nmol/kg bw, ip). Bone quality was assessed at the organ and tissue level by microCT, qXRI, 3-point bending, qBEI, nanoindentation, and Fourier-transform infrared microspectroscopy. [D-Ala2]GIP and liraglutide treatment did prevent loss of whole bone strength and cortical microstructure in the STZ-injected mice. However, tissue material properties were significantly improved in STZ-injected animals following treatment with [D-Ala2]GIP or liraglutide. Treatment of STZ-diabetic mice with [D-Ala(2) ]GIP or liraglutide was capable of significantly preventing deterioration of the quality of the bone matrix. Further studies are required to further elucidate the molecular mechanisms involved and to validate whether these findings can be translated to human patients. © 2015 Wiley Periodicals, Inc.

  7. A model for population dynamics of the mimetic butterfly Papilio polytes in the Sakishima Islands, Japan.

    PubMed

    Sekimura, Toshio; Fujihashi, Yuta; Takeuchi, Yasuhiro

    2014-11-21

    We present a mathematical model for population dynamics of the mimetic swallowtail butterfly Papilio polytes in the Sakishima Islands, Japan. The model includes four major variables, that is, population densities of three kinds of butterflies (two female forms f. cyrus, f. polytes and the unpalatable butterfly Pachliopta aristolochiae) and their predator. It is well-known that the non-mimic f. cyrus resembles and attracts the male most, and the mimic f. polytes mimics the model butterfly P. aristolochiae. Based on experimental evidence, we assume that two forms f. cyrus and f. polytes interact under intraspecific competition for resources including the male, and the growth rate of f. cyrus is higher than that of f. polytes. We further assume that both the benefit of mimicry for the mimic f. polytes and the cost for the model are dependent on their relative frequencies, i.e. the motality of the mimic by predation decreases with increase in frequency of the model, while the motality of the model increases as the frequency of the mimic increases. Taking the density-dependent effect through carrying capacity into account, we set up a model system consisting of three ordinary differential equations (ODEs), analyze it mathematically and provide computer simulations that confirm the analytical results. Our results reproduce field records on population dynamics of P. polytes in the Miyako-jima Island. They also explain the positive dependence of the relative abundance (RA) of the mimic on the advantage index (AI) of the mimicry in the Sakishima Islands defined in Section 2. Copyright © 2014 Elsevier Ltd. All rights reserved.

  8. Study on a 65-mer peptide mimetic enzyme with GPx and SOD dual function.

    PubMed

    Yin, Juxin; Zhuang, Jianjian; Lv, Shaowu; Mu, Ying

    2018-04-15

    Excessive reactive oxygen species (ROS) levels are harmful to the body. The peroxidase, GPx, and the superoxide dismutase, SOD, are important antioxidant enzymes for preventing ROS-induced damage. Se-CuZn-65P is an enzyme mimetic with dual GPx and SOD antioxidant function. However, currently, its production is mainly based on the cysteine auxotrophic expression technique, which is inefficient, expensive, and time consuming. In this study, we combined protein engineering and the chemical mutation method to synthesize Se-CuZn-65P. The DNA sequence encoding the 65 amino acid peptide with the desired sequence transformations to incorporate the SOD and the GPx catalytic sites was cloned and expressed in a soluble protein expression vector. The protein yield increased up to 152 mg/L, which is 10 times higher than in previous studies. The SOD and GPx activity of Se-CuZn-65P was high (1181 U/mg and 753 U/μmol, respectively). The binding constant of glutathione was 5.6 × 10 4  L·mol -1 , which shows that Se-CuZn-65P efficiently catalyzed hydrogen peroxide reduction by glutathione. Mitochondrial damage experiments confirmed the double protective role of the Se-CuZn-65P peptide and demonstrated functional synergy between the SOD and the GPx domains, which indicates its potential to be used in the treatment of ROS-related diseases. Our research may give a new thought to increase the yield of mimic. Copyright © 2018 John Wiley & Sons, Ltd.

  9. Mechanisms of vanadium action: insulin-mimetic or insulin-enhancing agent?

    PubMed

    Cam, M C; Brownsey, R W; McNeill, J H

    2000-10-01

    The demonstration that the trace element vanadium has insulin-like properties in isolated cells and tissues and in vivo has generated considerable enthusiasm for its potential therapeutic value in human diabetes. However, the mechanisms by which vanadium induces its metabolic effects in vivo remain poorly understood, and whether vanadium directly mimics or rather enhances insulin effects is considered in this review. It is clear that vanadium treatment results in the correction of several diabetes-related abnormalities in carbohydrate and lipid metabolism, and in gene expression. However, many of these in vivo insulin-like effects can be ascribed to the reversal of defects that are secondary to hyperglycemia. The observations that the glucose-lowering effect of vanadium depends on the presence of endogenous insulin whereas metabolic homeostasis in control animals appears not to be affected, suggest that vanadium does not act completely independently in vivo, but augments tissue sensitivity to low levels of plasma insulin. Another crucial consideration is one of dose-dependency in that insulin-like effects of vanadium in isolated cells are often demonstrated at high concentrations that are not normally achieved by chronic treatment in vivo and may induce toxic side effects. In addition, vanadium appears to be selective for specific actions of insulin in some tissues while failing to influence others. As the intracellular active forms of vanadium are not precisely defined, the site(s) of action of vanadium in metabolic and signal transduction pathways is still unknown. In this review, we therefore examine the evidence for and against the concept that vanadium is truly an insulin-mimetic agent at low concentrations in vivo. In considering the effects of vanadium on carbohydrate and lipid metabolism, we conclude that vanadium acts not globally, but selectively and by enhancing, rather than by mimicking the effects of insulin in vivo.

  10. Molecular weight effects upon the adhesive bonding of a mussel mimetic polymer.

    PubMed

    Jenkins, Courtney L; Meredith, Heather J; Wilker, Jonathan J

    2013-06-12

    Characterization of marine biological adhesives are teaching us how nature makes materials and providing new ideas for synthetic systems. One of the most widely studied adhering animals is the marine mussel. This mollusk bonds to wet rocks by producing an adhesive from cross-linked proteins. Several laboratories are now making synthetic mimics of mussel adhesive proteins, with 3,4-dihydroxyphenylalanine (DOPA) or similar molecules pendant from polymer chains. In select cases, appreciable bulk bonding results, with strengths as high as commercial glues. Polymer molecular weight is amongst several parameters that need to be examined in order to both understand biomimetic adhesion as well as to maximize performance. Experiments presented here explore how the bulk adhesion of a mussel mimetic polymer varies as a function of molecular weight. Systematic structure-function studies were carried out both with and without the presence of an oxidative cross-linker. Without cross-linking, higher molecular weights generally afforded higher adhesion. When a [N(C4H9)4](IO4) cross-linker was added, adhesion peaked at molecular weights of ~50,000-65,000 g/mol. These data help to illustrate how changes to the balance of cohesion versus adhesion influence bulk bonding. Mussel adhesive plaques achieve this balance by incorporating several proteins with molecular weights ranging from 6000 to 110,000 g/mol. To mimic these varied proteins we made a blend of polymers containing a range of molecular weights. Interestingly, this blend adhered more strongly than any of the individual polymers when cross-linked with [N(C4H9)4](IO4). These results are helping us to both understand the origins of biological materials as well as design high performance polymers.

  11. The daunorubicin interplay with mimetic model membranes of cancer cells: A biophysical interpretation.

    PubMed

    Alves, Ana Catarina; Ribeiro, Daniela; Horta, Miguel; Lima, José L F C; Nunes, Cláudia; Reis, Salette

    2017-05-01

    The present work aimed to study the interactions between the anticancer drug daunorubicin and lipid membrane mimetic models of cancer cells composed by their most representative classes of phospholipids, with different degrees of complexity. Regarding these anticancer drug-membrane interactions, several biophysical parameters were assessed using liposomes (LUVs) composed of different molar ratios of DMPC, DOPC, DPPS, DOPE and Chol. In this context, daunorubicin's membrane concentration was determined by calculating its partition coefficient (Kp) between liposomes and water using derivative UV/vis spectrophotometry at 37°C and pH6.3, a typical tumoral microenvironment. Characterization of the zeta potential of such model membranes, in both the absence and presence of the compound, was accomplished through Electrophoretic Light Scattering (ELS). Fluorescence quenching studies, which determine the location of the drug within the bilayer, were carried out using liposomes labelled with DPH and TMA-DPH, fluorescent probes with known membrane position. Temperature dependent steady-state anisotropy assays were also performed to measure the daunorubicin effect on the membranes' microviscosity. The overall results support that daunorubicin permeation depends on the phospholipid membrane composition and causes alterations in the biophysical properties of the bilayers, namely in the membrane fluidity. The interaction of daunorubicin with the studied phospholipids is mainly driven by electrostatic and hydrophobic interactions. These insights demonstrated that not only membranes can affect daunorubicin accumulation in cells but the compound can alter the properties of membranes. The changes produced by daunorubicin on the lipid structure may constitute an additional mechanism of action, which might lead to modifications in the location and, consequently, the activity of membrane signaling proteins. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Bio-Mimetics of Disaster Anticipation-Learning Experience and Key-Challenges.

    PubMed

    Tributsch, Helmut

    2013-03-19

    Anomalies in animal behavior and meteorological phenomena before major earthquakes have been reported throughout history. Bio-mimetics or bionics aims at learning disaster anticipation from animals. Since modern science is reluctant to address this problem an effort has been made to track down the knowledge available to ancient natural philosophers. Starting with an archaeologically documented human sacrifice around 1700 B.C. during the Minoan civilization immediately before a large earthquake, which killed the participants, earthquake prediction knowledge throughout antiquity is evaluated. Major practical experience with this phenomenon has been gained from a Chinese earthquake prediction initiative nearly half a century ago. Some quakes, like that of Haicheng, were recognized in advance. However, the destructive Tangshan earthquake was not predicted, which was interpreted as an inherent failure of prediction based on animal phenomena. This is contradicted on the basis of reliable Chinese documentation provided by the responsible earthquake study commission. The Tangshan earthquake was preceded by more than 2,000 reported animal anomalies, some of which were of very dramatic nature. They are discussed here. Any physical phenomenon, which may cause animal unrest, must involve energy turnover before the main earthquake event. The final product, however, of any energy turnover is heat. Satellite based infrared measurements have indeed identified significant thermal anomalies before major earthquakes. One of these cases, occurring during the 2001 Bhuj earthquake in Gujarat, India, is analyzed together with parallel animal anomalies observed in the Gir national park. It is suggested that the time window is identical and that both phenomena have the same geophysical origin. It therefore remains to be demonstrated that energy can be released locally before major earthquake events. It is shown that by considering appropriate geophysical feedback processes, this is

  13. Thioredoxin-mimetic peptides (TXM) inhibit inflammatory pathways associated with high-glucose and oxidative stress.

    PubMed

    Lejnev, Katia; Khomsky, Lena; Bokvist, Krister; Mistriel-Zerbib, Shani; Naveh, Tahel; Farb, Thomas Bradley; Alsina-Fernandez, Jorge; Atlas, Daphne

    2016-10-01

    Impaired insulin signaling and the associated insulin-resistance in liver, adipose tissue, and skeletal muscle, represents a hallmark of the pathogenesis of type 2-diabetes-mellitus. Here we show that in the liver of db/db mice, a murine model of obesity, type 2 diabetes, and dyslipidemia, the elevated activities of mitogen-activated protein kinases (MAPK; ERK1/2 and p38 MAPK ), and Akt/PKB are abolished by rosiglitazone-treatment, which normalizes blood glucose in db/db mice. This is unequivocal evidence of a functional link between the activation of the MAPK specific inflammatory-pathway and high-blood sugar. A similar reduction in ERK1/2, p38 MAPK , and Akt activities but without affecting blood-glucose was observed in the liver of db/db mice treated with a molecule that mimics the action of thioredoxin, called thioredoxin-mimetic peptide (TXM). N-Acetyl-Cys-Pro-Cys-amide (TXM-CB3) is a free radical scavenger, a reducing and denitrosylating reagent that protects the cells from early death induced by inflammatory pathways. TXM-CB3 also lowered MAPK signaling activated by the disruption of the thioredoxin-reductase-thioredoxin (Trx-TrxR) redox-system and restored Akt activity in rat hepatoma FAO cells. Similarly, two other TXM-peptides, N-Acetyl-Cys-Met-Lys-Cys-amide (TXM-CB13; DY70), and N-Acetyl-Cys-γGlu-Cys-Cys-amide (TXM-CB16; DY71), lowered insulin- and oxidative stress-induced ERK1/2 activation, and rescued HepG2 cells from cell death. The potential impact of TXM-peptides on inhibiting inflammatory pathways associated with high-glucose could be effective in reversing low-grade inflammation. TXM-peptides might also have the potential to improve insulin resistance by protecting from posttranslational modifications like nitrosylation. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Reactivation of Smac-mediated apoptosis in chronic lymphocytic leukemia cells: mechanistic studies of Smac mimetic

    PubMed Central

    Balakrishnan, Kumudha; Fu, Min; Onida, Francesco; Wierda, William G.; Keating, Michael J.; Gandhi, Varsha

    2016-01-01

    Dysfunctional apoptotic machinery is a hallmark feature of chronic lymphocytic leukemia (CLL). Accordingly, targeting apoptosis regulators has been proven a rational approach for CLL treatment. We show that CLL lymphocytes express high levels of XIAP, cIAP1, and cIAP2 compared to normal lymphocytes. Smac mimetic, Smac066, designed to bind to BIR3-domain of IAPs, induce apoptosis in primary CLL cells (n=71; p<0.0001), irrespective of prognostic markers. Apoptosis was mediated by diminished levels of IAPs (XIAP-p=0.02; cIAP-p<0.0001) and increased activation of caspases-8, −9, −3. The caspase-cleavage was in direct association with the levels of apoptosis (r2=0.8 for caspases-8, −9, −3). Correlative analysis revealed a direct relationship between reduction in IAPs and degree of apoptosis (r2=0.6 (XIAP); 0.5 (cIAP2)). There was a strong association between apoptosis, IAP-degradation, and concurrent caspase-activation. Pan-caspase inhibitor Z-Vad-fmk reversed the degradation of Mcl-1, but not IAPs suggesting that smac066 is selective to IAPs, however, Mcl-1 degradation is through caspase-mediated cleavage. Immunoprecipitation experiments revealed physical interaction between caspase-3 and XIAP that was disrupted by smac066. Importantly, XIAP and cIAP2 were markedly induced in bone-marrow and lymph-node microenvironments, providing a basis for IAP antagonists as anti-tumor agents in CLL. Smac066 synergized with ABT-737, revealing a mechanistic rationale to jointly target BH3 and BIR3 domains. PMID:27223062

  15. Reactivation of Smac-mediated apoptosis in chronic lymphocytic leukemia cells: mechanistic studies of Smac mimetic.

    PubMed

    Balakrishnan, Kumudha; Fu, Min; Onida, Francesco; Wierda, William G; Keating, Michael J; Gandhi, Varsha

    2016-06-28

    Dysfunctional apoptotic machinery is a hallmark feature of chronic lymphocytic leukemia (CLL). Accordingly, targeting apoptosis regulators has been proven a rational approach for CLL treatment. We show that CLL lymphocytes express high levels of XIAP, cIAP1, and cIAP2 compared to normal lymphocytes. Smac mimetic, Smac066, designed to bind to BIR3-domain of IAPs, induce apoptosis in primary CLL cells (n=71; p<0.0001), irrespective of prognostic markers. Apoptosis was mediated by diminished levels of IAPs (XIAP-p=0.02; cIAP-p<0.0001) and increased activation of caspases-8,-9,-3. The caspase-cleavage was in direct association with the levels of apoptosis (r2=0.8 for caspases-8,-9,-3). Correlative analysis revealed a direct relationship between reduction in IAPs and degree of apoptosis (r2=0.6 (XIAP); 0.5 (cIAP2)). There was a strong association between apoptosis, IAP-degradation, and concurrent caspase-activation. Pan-caspase inhibitor Z-Vad-fmk reversed the degradation of Mcl-1, but not IAPs suggesting that smac066 is selective to IAPs, however, Mcl-1 degradation is through caspase-mediated cleavage. Immunoprecipitation experiments revealed physical interaction between caspase-3 and XIAP that was disrupted by smac066. Importantly, XIAP and cIAP2 were markedly induced in bone-marrow and lymph-node microenvironments, providing a basis for IAP antagonists as anti-tumor agents in CLL. Smac066 synergized with ABT-737, revealing a mechanistic rationale to jointly target BH3 and BIR3 domains.

  16. Novel Synthetic SOD/Catalase Mimetics Can Mitigate Capillary Endothelial Cell Apoptosis Caused by Ionizing Radiation

    PubMed Central

    Vorotnikova, Ekaterina; Rosenthal, Rosalind A.; Tries, Mark; Doctrow, Susan R.; Braunhut, Susan J.

    2015-01-01

    Numerous in vitro and in vivo studies have shown that the endothelial cells of the microvasculature of the lung and kidney are damaged by exposure to ionizing radiation, and this sustained endothelial cell injury is involved in the early and late radiation effects observed in these tissues. It is well accepted that ionizing radiation causes the generation of reactive oxygen species during exposure that results in damage to DNA and cellular organelles. It is more controversial, however, whether additional biochemical events or long-lived radicals occur and persist postirradiation that amplify and initiate new forms of cellular damage. Two families of Eukarion (EUK) compounds have been synthesized that possess superoxide dismutase (SOD), catalase and peroxidase activities. The Mn porphyrins are available orally whereas the salen Mn complexes are administered by injection. In the present study we have examined the ability of these SOD/catalase mimetics to prevent apoptosis of endothelial cells when administered 1 h postirradiation (mitigation). A range of salen Mn complex (EUK-189 and EUK-207) and Mn porphyrins (EUK-418, -423, -425, -450, -451, -452, -453) were used to treat endothelial cells 1 h after the cells received 2–20 Gy ionizing radiation in vitro. Two lead compounds, EUK-207 at a dose of 30 μM and EUK-451 at a dose of 10 μM, exhibited low toxicity and mitigated radiation-induced apoptosis. Future animal studies will test whether these compounds protect when administered after radiation exposure as would be done after a radiological accident or a terrorism event. PMID:20518654

  17. Noninvasive imaging of radiolabeled exosome-mimetic nanovesicle using (99m)Tc-HMPAO.

    PubMed

    Hwang, Do Won; Choi, Hongyoon; Jang, Su Chul; Yoo, Min Young; Park, Ji Yong; Choi, Na Eun; Oh, Hyun Jeong; Ha, Seunggyun; Lee, Yun-Sang; Jeong, Jae Min; Gho, Yong Song; Lee, Dong Soo

    2015-10-26

    Exosomes known as nano-sized extracellular vesicles attracted recent interests due to their potential usefulness in drug delivery. Amid remarkable advances in biomedical applications of exosomes, it is crucial to understand in vivo distribution and behavior of exosomes. Here, we developed a simple method for radiolabeling of macrophage-derived exosome-mimetic nanovesicles (ENVs) with (99m)Tc-HMPAO under physiologic conditions and monitored in vivo distribution of (99m)Tc-HMPAO-ENVs using SPECT/CT in living mice. ENVs were produced from the mouse RAW264.7 macrophage cell line and labeled with (99m)Tc-HMPAO for 1 hr incubation, followed by removal of free (99m)Tc-HMPAO. SPECT/CT images were serially acquired after intravenous injection to BALB/c mouse. When ENVs were labeled with (99m)Tc-HMPAO, the radiochemical purity of (99m)Tc-HMPAO-ENVs was higher than 90% and the expression of exosome specific protein (CD63) did not change in (99m)Tc-HMPAO-ENVs. (99m)Tc-HMPAO-ENVs showed high serum stability (90%) which was similar to that in phosphate buffered saline until 5 hr. SPECT/CT images of the mice injected with (99m)Tc-HMPAO-ENVs exhibited higher uptake in liver and no uptake in brain, whereas mice injected with (99m)Tc-HMPAO showed high brain uptake until 5 hr. Our noninvasive imaging of radiolabeled-ENVs promises better understanding of the in vivo behavior of exosomes for upcoming biomedical application.

  18. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic

    SciTech Connect

    Thompson, Aaron A.; Liu, Wei; Chun, Eugene

    2012-07-11

    Members of the opioid receptor family of G-protein-coupled receptors (GPCRs) are found throughout the peripheral and central nervous system, where they have key roles in nociception and analgesia. Unlike the 'classical' opioid receptors, {delta}, {kappa} and {mu} ({delta}-OR, {kappa}-OR and {mu}-OR), which were delineated by pharmacological criteria in the 1970s and 1980s, the nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP, also known as ORL-1) was discovered relatively recently by molecular cloning and characterization of an orphan GPCR. Although it shares high sequence similarity with classical opioid GPCR subtypes ({approx}60%), NOP has a markedly distinct pharmacology, featuring activation by the endogenous peptidemore » N/OFQ, and unique selectivity for exogenous ligands. Here we report the crystal structure of human NOP, solved in complex with the peptide mimetic antagonist compound-24 (C-24) (ref. 4), revealing atomic details of ligand-receptor recognition and selectivity. Compound-24 mimics the first four amino-terminal residues of the NOP-selective peptide antagonist UFP-101, a close derivative of N/OFQ, and provides important clues to the binding of these peptides. The X-ray structure also shows substantial conformational differences in the pocket regions between NOP and the classical opioid receptors {kappa} (ref. 5) and {mu} (ref. 6), and these are probably due to a small number of residues that vary between these receptors. The NOP-compound-24 structure explains the divergent selectivity profile of NOP and provides a new structural template for the design of NOP ligands.« less

  19. Strategy To Fabricate Naked-Eye Readout Ultrasensitive Plasmonic Nanosensor Based on Enzyme Mimetic Gold Nanoclusters.

    PubMed

    Zhao, Qian; Huang, Haowen; Zhang, Lingyang; Wang, Linqian; Zeng, Yunlong; Xia, Xiaodong; Liu, Fengping; Chen, Yi

    2016-01-19

    It is broadly interesting but remains a big challenge to explore nanomaterials-based methods to enable naked-eye observation and determination of ultratrace biomarkers and drugs. In this study, we developed a straightforward and extendable plasmonic nanosensor to enable visually quantitative determination of ultratrace target molecules through combining the use of enzyme-mimetic gold nanoclusters (AuNCs). Starting from sandwiched antibody-antigen (i.e., an analyte)-antibody structure, we conjugated AuNCs on the outer layer antibody to catalyze the decomposition of hydrogen peroxide used to reduce HAuCl4 into gold nanopartilces (AuNPs) for naked eye readout. This strategy is in theory applicable to all immunoreactions available and the protocol proposed to attach AuNCs onto an antibody is suitable to all proteins. The applicability of this type of nanosensor was validated by the determination of various ultratrace analytes such as protein avidin, breast cancer antigen, thyroid hormone, and even methamphetamine (MA), giving a naked-eye-readout limit of detection (LOD), down to 1.0 × 10(-20) M protein avidin, 7.52 × 10(-14) U/mL breast cancer antigen 15-3, 2.0 × 10(-15) mg/mL 3,5,3'-L-triiodothyronine and 2.3 × 10(-18) mg/mL MA. This strategy is thus considered an ultrasensitive way to fabricate plasmonic nanosensors, having wide and invaluable application potential in clinical, biological, and environmental studies, and in food quality control.

  20. Three-Dimensional Elastomeric Scaffolds Designed with Cardiac-Mimetic Structural and Mechanical Features

    PubMed Central

    Neal, Rebekah A.; Jean, Aurélie; Park, Hyoungshin; Wu, Patrick B.; Hsiao, James; Engelmayr, George C.; Langer, Robert

    2013-01-01

    Tissue-engineered constructs, at the interface of material science, biology, engineering, and medicine, have the capacity to improve outcomes for cardiac patients by providing living cells and degradable biomaterials that can regenerate the native myocardium. With an ultimate goal of both delivering cells and providing mechanical support to the healing heart, we designed three-dimensional (3D) elastomeric scaffolds with (1) stiffnesses and anisotropy mimicking explanted myocardial specimens as predicted by finite-element (FE) modeling, (2) systematically varied combinations of rectangular pore pattern, pore aspect ratio, and strut width, and (3) structural features approaching tissue scale. Based on predicted mechanical properties, three scaffold designs were selected from eight candidates for fabrication from poly(glycerol sebacate) by micromolding from silicon wafers. Large 20×20 mm scaffolds with high aspect ratio features (5:1 strut height:strut width) were reproducibly cast, cured, and demolded at a relatively high throughput. Empirically measured mechanical properties demonstrated that scaffolds were cardiac mimetic and validated FE model predictions. Two-layered scaffolds providing fully interconnected pore networks were fabricated by layer-by-layer assembly. C2C12 myoblasts cultured on one-layered scaffolds exhibited specific patterns of cell elongation and interconnectivity that appeared to be guided by the scaffold pore pattern. Neonatal rat heart cells cultured on two-layered scaffolds for 1 week were contractile, both spontaneously and in response to electrical stimulation, and expressed sarcomeric α-actinin, a cardiac biomarker. This work not only demonstrated several scaffold designs that promoted functional assembly of rat heart cells, but also provided the foundation for further computational and empirical investigations of 3D elastomeric scaffolds for cardiac tissue engineering. PMID:23190320

  1. Continuous volatile fatty acid production from lignocellulosic biomass by a novel rumen-mimetic bioprocess.

    PubMed

    Agematu, Hitosi; Takahashi, Takehiko; Hamano, Yoshio

    2017-11-01

    Lignocellulosic biomass is an attractive source of biofuels and biochemicals, being abundant in various plant sources. However, processing this type of biomass requires hydrolysis of cellulose. The proposed rumen-mimetic bioprocess consists of dry-pulverization of lignocellulosic biomass and pH-controlled continuous cultivation of ruminal bacteria using ammonium as a nitrogen source. In this study, ruminal bacteria were continuously cultivated for over 60 days and used to digest microcrystalline cellulose, rice straw, and Japanese cedar to produce volatile fatty acids (VFAs). The ruminal bacteria grew well in the chemically defined medium. The amounts of VFAs produced from 20 g of cellulose, rice straw, and Japanese cedar were 183 ± 29.7, 69.6 ± 12.2, and 21.8 ± 12.9 mmol, respectively. Each digestion completed within 24 h. The carbon yield was 60.6% when 180 mmol of VFAs was produced from 20 g of cellulose. During the cultivation, the bacteria were observed to form flocs that enfolded the feed particles. These flocs likely contain all of the bacterial species necessary to convert lignocellulosic biomass to VFAs and microbial protein symbiotically. Denaturing gradient gel electrophoresis (DGGE) analysis of PCR-amplified 16S rDNA fragments revealed that the bacterial community was relatively stable after 1 week in cultivation, though it was different from the original community structure. Furthermore, sequence analysis of the DGGE bands indicates that the microbial community includes a cellulolytic bacterium, a bacterium acting synergistically with cellulolytic bacteria, and a propionate-producing bacterium, as well as other anaerobic bacteria. Copyright © 2017 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  2. Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties

    PubMed Central

    Wool, Geoffrey D.; Reardon, Catherine A.; Getz, Godfrey S.

    2008-01-01

    We hypothesize that apolipoprotein A-I (apoA-I) mimetic peptides better mimicking the punctuated α-helical repeats of full-length apoA-I are more anti-inflammatory and anti-atherogenic. This study compares a monomeric apoA-I mimetic helix to three different tandem helix peptides in vitro: 4F (18 mer), 4F-proline-4F (37 mer, Pro), 4F-alanine-4F (37 mer, Ala), and 4F-KVEPLRA-4F [the human apoA-I 4/5 interhelical sequence (IHS), 43 mer]. All peptides cleared turbid lipid suspensions, with 4F being most effective. In contrast to lipid clearance, tandem peptides were more effective at remodeling mouse HDL. All four peptides displaced apoA-I and apoE from the HDL, leaving a larger particle containing apoA-II and peptide. Peptide-remodeled HDL particles show no deficit in ABCG1 cholesterol efflux despite the loss of the majority of apoA-I. Tandem peptides show greater ability to efflux cholesterol from lipid-loaded murine macrophages, compared with 4F. Although 4F inhibited oxidation of purified mouse LDL, the Ala tandem peptide increased oxidation. We compared several tandem 4F-based peptides with monomeric 4F in assays that correlated with suggested anti-inflammatory/anti-atherogenic pathways. Tandem 4F-based peptides, which better mimic full-length apoA-I, exceed monomeric 4F in HDL remodeling and cholesterol efflux but not LDL oxidation protection. In addition, apoA-I mimetic peptides may increase reverse cholesterol transport through both ABCA1 as well as ABCG1 pathways. PMID:18323574

  3. A novel drug delivery system for type 1 diabetes: insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex.

    PubMed

    Karmaker, Subarna; Saha, Tapan K; Yoshikawa, Yutaka; Yasui, Hiroyuki; Sakurai, Hiromu

    2006-09-01

    Insulin-mimetic vanadyl-poly(gamma-glutamic acid) complex, VO-gamma-PGA, is proposed as a novel drug delivery system for treating type 1 diabetic animals. The structure of VO-gamma-PGA in solution as well as in solid state was analyzed by electronic absorption, infra-red, and electron spin resonance spectra, and proposed that the equatorial coordination mode of VO(2+) is in either carboxylate(O)-VO-(OH(2))(3) or 2 carboxylate(O(2))-VO-(OH(2))(2). In vitro insulin-mimetic activity, metallokinetic feature in the blood of healthy rats, and in vivo normoglycemic effect of the complex prepared in solution were evaluated in streptozotocin(STZ)-induced type 1 diabetic mice, and these effects were compared with those of a solution containing only VOSO(4) as a positive control. The in vitro insulin-mimetic activity of VO-gamma-PGA was examined by determining both inhibition of free fatty acid (FFA) release and glucose uptake in isolated rat adipocytes, in which the concentration of VO-gamma-PGA for 50% inhibition of FFA release was significantly lower than that of VOSO(4). Metallokinetic study suggested that the bioavailability of VO-gamma-PGA complex was much higher than that of VOSO(4). The complex showed a significant hypoglycemic activity within at least 4h after a single oral administration, the effect being sustained for at least 24h. Furthermore, VO-gamma-PGA normalized the hyperglycemia in STZ-mice within 3 days when it was given orally at doses of 5-10mgVkg(-1) body mass for 16 days. The improvement in diabetes was also supported by the results on oral glucose tolerance test, HbA(1c) levels, and blood pressure.

  4. MET-Independent Lung Cancer Cells Evading EGFR Kinase Inhibitors are Therapeutically Susceptible to BH3 Mimetic Agents

    PubMed Central

    Fan, Weiwen; Tang, Zhe; Yin, Lihong; Morrison, Bei; Hafez-Khayyata, Said; Fu, Pingfu; Huang, Honglian; Bagai, Rakesh; Jiang, Shan; Kresak, Adam; Howell, Scott; Vasanji, Amit; Flask, Chris A.; Halmos, Balazs; Koon, Henry; Ma, Patrick C.

    2011-01-01

    Targeted therapies for cancer are inherently limited by the inevitable recurrence of resistant disease after initial responses. To define early molecular changes within residual tumor cells that persist after treatment, we analyzed drug sensitive lung adenocarcinoma cell lines exposed to reversible or irreversible EGFR inhibitors, alone or in combination with MET kinase inhibitors, to characterize the adaptive response that engenders drug resistance. Tumor cells displaying early resistance exhibited dependence on MET-independent activation of BCL-2/BCL-XL survival signaling. Further, such cells displayed a quiescence-like state associated with greatly retarded cell proliferation and cytoskeletal functions that were readily reversed after withdrawal of targeted inhibitors. Findings were validated in a xenograft model, demonstrating BCL-2 induction and p-STAT3[Y705] activation within the residual tumor cells surviving the initial anti-tumor response to targeted therapies. Disrupting the mitochondrial BCL-2/BCL-XL antiapoptotic machinery in early survivor cells using BH3 mimetic agents such as ABT-737, or by dual RNAi-mediated knockdown of BCL-2/BCL-XL, was sufficient to eradicate the early resistant lung tumor cells evading targeted inhibitors. Similarly, in a xenograft model the preemptive co-treatment of lung tumor cells with an EGFR inhibitor and a BH3 mimetic eradicated early TKI-resistant evaders and ultimately achieved a more durable response with prolonged remission. Our findings prompt prospective clinical investigations using BH3-mimetics combined with targeted receptor kinase inhibitors to optimize and improve clinical outcomes in lung cancer treatment. PMID:21555370

  5. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds

    PubMed Central

    Madani, Navid; Princiotto, Amy M.; Easterhoff, David; Bradley, Todd; Luo, Kan; Williams, Wilton B.; Liao, Hua-Xin; Moody, M. Anthony; Phad, Ganesh E.; Vázquez Bernat, Néstor; Melillo, Bruno; Santra, Sampa; Smith, Amos B.; Karlsson Hedestam, Gunilla B.; Haynes, Barton

    2016-01-01

    ABSTRACT The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. IMPORTANCE Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in

  6. Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds.

    PubMed

    Madani, Navid; Princiotto, Amy M; Easterhoff, David; Bradley, Todd; Luo, Kan; Williams, Wilton B; Liao, Hua-Xin; Moody, M Anthony; Phad, Ganesh E; Vázquez Bernat, Néstor; Melillo, Bruno; Santra, Sampa; Smith, Amos B; Karlsson Hedestam, Gunilla B; Haynes, Barton; Sodroski, Joseph

    2016-05-15

    The human immunodeficiency virus (HIV-1) envelope glycoproteins (Env) mediate virus entry through a series of complex conformational changes triggered by binding to the receptors CD4 and CCR5/CXCR4. Broadly neutralizing antibodies that recognize conserved Env epitopes are thought to be an important component of a protective immune response. However, to date, HIV-1 Env immunogens that elicit broadly neutralizing antibodies have not been identified, creating hurdles for vaccine development. Small-molecule CD4-mimetic compounds engage the CD4-binding pocket on the gp120 exterior Env and induce Env conformations that are highly sensitive to neutralization by antibodies, including antibodies directed against the conserved Env region that interacts with CCR5/CXCR4. Here, we show that CD4-mimetic compounds sensitize primary HIV-1 to neutralization by antibodies that can be elicited in monkeys and humans within 6 months by several Env vaccine candidates, including gp120 monomers. Monoclonal antibodies directed against the gp120 V2 and V3 variable regions were isolated from the immunized monkeys and humans; these monoclonal antibodies neutralized a primary HIV-1 only when the virus was sensitized by a CD4-mimetic compound. Thus, in addition to their direct antiviral effect, CD4-mimetic compounds dramatically enhance the HIV-1-neutralizing activity of antibodies that can be elicited with currently available immunogens. Used as components of microbicides, the CD4-mimetic compounds might increase the protective efficacy of HIV-1 vaccines. Preventing HIV-1 transmission is a high priority for global health. Eliciting antibodies that can neutralize transmitted strains of HIV-1 is difficult, creating problems for the development of an effective vaccine. We found that small-molecule CD4-mimetic compounds sensitize HIV-1 to antibodies that can be elicited in vaccinated humans and monkeys. These results suggest an approach to prevent HIV-1 sexual transmission in which a virus

  7. Study on distribution of terminal branches of the facial nerve in mimetic muscles (orbicularis oculi muscle and orbicularis oris muscle).

    PubMed

    Mitsukawa, Nobuyuki; Moriyama, Hiroshi; Shiozawa, Kei; Satoh, Kaneshige

    2014-01-01

    There have been many anatomical reports to date regarding the course of the facial nerve to the mimetic muscles. However, reports are relatively scarce on the detailed distribution of the terminal branches of the facial nerve to the mimetic muscles. In this study, we performed detailed examination of the terminal facial nerve branches to the mimetic muscles, particularly the branches terminating in the orbicularis oculi muscle and orbicularis oris muscle. Examination was performed on 25 Japanese adult autopsy cases, involving 25 hemifaces. The mean age was 87.4 years (range, 60-102 years). There were 12 men and 13 women (12 left hemifaces and 13 right hemifaces). In each case, the facial nerve was exposed through a preauricular skin incision. The main trunk of the facial nerve was dissected from the stylomastoid foramen. A microscope was used to dissect the terminal branches to the periphery and observe them. The course and distribution were examined for all terminal branches of the facial nerve. However, focus was placed on the course and distribution of the zygomatic branch, buccal branch, and mandibular branch to the orbicularis oculi muscle and orbicularis oris muscle. The temporal branch was distributed to the orbicularis oculi muscle in all cases and the marginal mandibular branch was distributed to the orbicularis oris muscle in all cases. The zygomatic branch was distributed to the orbicularis oculi muscle in all cases, but it was also distributed to the orbicularis oris muscle in 10 of 25 cases. The buccal branch was not distributed to the orbicularis oris muscle in 3 of 25 cases, and it was distributed to the orbicularis oculi muscle in 8 cases. There was no significant difference in the variations. The orbicularis oculi muscle and orbicularis oris muscle perform particularly important movements among the facial mimetic muscles. According to textbooks, the temporal branch and zygomatic branch innervate the orbicularis oculi muscle, and the buccal branch

  8. Design and screening of syringic acid analogues as BAX activators-An in silico approach to discover "BH3 mimetics".

    PubMed

    Cheemanapalli, Srinivasulu; C M, Anuradha; Pakala, Suresh Babu; Chitta, Suresh Kumar

    2018-03-09

    Although BAX, which is a molecular hit squad that incentive apoptosis was found to be an attractive emerging target for anticancer agents. The molecular mechanism of small molecules/peptides involved in the BAX activation was remain unknown. The present focus of the study is to identification and development of novel molecules which are precisely activates BAX mediated apoptosis. In this process we identified some syringic acid analogues associated with the BAX hydrophobic groove by a virtual-screen approach. Results from the docking studies revealed that, SA1, SA9, SA10, SA14 and SA21 analogues have shown good interaction with BAX trigger site, of which SA10 and SA14 bound specifically with Lys21 at α1 helix of BAX, a critical residue involved in BAX activation. All docking calculations of SA analogues were compared with clinically tested BH3 mimetics. In this entire in silico study, SA analogous have performed an ideal binding interactions with BAX compared to BH3 mimetics. Further, in silico point mutation of BAX-Lys21 to Glu21 resulted in structural change in BAX and showed reduced binding energy and hydrogen bond interactions of the selected ligands. Based on these findings, we propose that virtual screening and mutation analysis of BAX is found to be the critical advance method towards the discovery of novel anticancer therapeutics. Copyright © 2018 Elsevier Ltd. All rights reserved.

  9. A novel Smac mimetic APG-1387 demonstrates potent antitumor activity in nasopharyngeal carcinoma cells by inducing apoptosis.

    PubMed

    Li, Ning; Feng, Lin; Han, Hui-Qiong; Yuan, Jing; Qi, Xue-Kang; Lian, Yi-Fan; Kuang, Bo-Hua; Zhang, Yu-Chen; Deng, Cheng-Cheng; Zhang, Hao-Jiong; Yao, You-Yuan; Xu, Miao; He, Gui-Ping; Zhao, Bing-Chun; Gao, Ling; Feng, Qi-Sheng; Chen, Li-Zhen; Yang, Lu; Yang, Dajun; Zeng, Yi-Xin

    2016-10-10

    Despite advances in the development of radiation against nasopharyngeal carcinoma (NPC), the management of advanced NPC remains a challenge. Smac mimetics are designed to neutralize inhibitor of apoptosis (IAP) proteins, thus reactivating the apoptotic program in cancer cells. In this study, we investigated the effect of a novel bivalent Smac mimetic APG-1387 in NPC. In vitro, APG-1387 in combination with TNF-α potently decreased NPC cell viability by inducing apoptosis in majority of NPC cell lines. The in vitro antitumor effect was RIPK1-dependent, whereas it was independent on IAPs, USP11, or EBV. Of note, the inhibition of NF-κB or AKT pathway rendered resistant NPC cells responsive to the treatment of APG-1387/TNF-α. In vivo, APG-1387 displayed antitumor activity as a single agent at well-tolerated doses, even in an in vitro resistant cell line. In summary, our results demonstrate that APG-1387 exerts a potent antitumor effect on NPC. These findings support clinical evaluation of APG-1387 as a potential treatment for advanced NPC. Copyright © 2016. Published by Elsevier Ireland Ltd.

  10. Effect of Vanadyl Rosiglitazone, a New Insulin-Mimetic Vanadium Complexes, on Glucose Homeostasis of Diabetic Mice.

    PubMed

    Jiang, Pingzhe; Dong, Zhen; Ma, Baicheng; Ni, Zaizhong; Duan, Huikun; Li, Xiaodan; Wang, Bin; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Li, Minggang

    2016-11-01

    Diabetes has been cited as the most challenging health problem in the twenty-first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes.

  11. Influence of Block Copolymerization on the Antifreeze Protein Mimetic Ice Recrystallization Inhibition Activity of Poly(vinyl alcohol).

    PubMed

    Congdon, Thomas R; Notman, Rebecca; Gibson, Matthew I

    2016-09-12

    Antifreeze (glyco) proteins are produced by many cold-acclimatized species to enable them to survive subzero temperatures. These proteins have multiple macroscopic effects on ice crystal growth which makes them appealing for low-temperature applications-from cellular cryopreservation to food storage. Poly(vinyl alcohol) has remarkable ice recrystallization inhibition activity, but its mode of action is uncertain as is the extent at which it can be incorporated into other high-order structures. Here the synthesis and characterization of well-defined block copolymers containing poly(vinyl alcohol) and poly(vinylpyrrolidone) by RAFT/MADIX polymerization is reported, as new antifreeze protein mimetics. The effect of adding a large second hydrophilic block is studied across a range of compositions, and it is found to be a passive component in ice recrystallization inhibition assays, enabling retention of all activity. In the extreme case, a block copolymer with only 10% poly(vinyl alcohol) was found to retain all activity, where statistical copolymers of PVA lose all activity with very minor changes to composition. These findings present a new method to increase the complexity of antifreeze protein mimetic materials, while retaining activity, and also to help understand the underlying mechanisms of action.

  12. A spectral mimetic least-squares method for the Stokes equations with no-slip boundary condition

    DOE PAGES

    Gerritsma, Marc; Bochev, Pavel

    2016-03-22

    Formulation of locally conservative least-squares finite element methods (LSFEMs) for the Stokes equations with the no-slip boundary condition has been a long standing problem. Existing LSFEMs that yield exactly divergence free velocities require non-standard boundary conditions (Bochev and Gunzburger, 2009 [3]), while methods that admit the no-slip condition satisfy the incompressibility equation only approximately (Bochev and Gunzburger, 2009 [4, Chapter 7]). Here we address this problem by proving a new non-standard stability bound for the velocity–vorticity–pressure Stokes system augmented with a no-slip boundary condition. This bound gives rise to a norm-equivalent least-squares functional in which the velocity can be approximatedmore » by div-conforming finite element spaces, thereby enabling a locally-conservative approximations of this variable. Here, we also provide a practical realization of the new LSFEM using high-order spectral mimetic finite element spaces (Kreeft et al., 2011) and report several numerical tests, which confirm its mimetic properties.« less

  13. SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells.

    PubMed

    Langdon, Casey G; Wiedemann, Norbert; Held, Matthew A; Mamillapalli, Ramanaiah; Iyidogan, Pinar; Theodosakis, Nicholas; Platt, James T; Levy, Frederic; Vuagniaux, Gregoire; Wang, Shaomeng; Bosenberg, Marcus W; Stern, David F

    2015-11-10

    Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c-IAP1, c-IAP2, and XIAP. Non-canonical NF-κB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143-containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here.

  14. SMAC mimetic Debio 1143 synergizes with taxanes, topoisomerase inhibitors and bromodomain inhibitors to impede growth of lung adenocarcinoma cells

    PubMed Central

    Held, Matthew A.; Mamillapalli, Ramanaiah; Iyidogan, Pinar; Theodosakis, Nicholas; Platt, James T.; Levy, Frederic; Vuagniaux, Gregoire; Wang, Shaomeng; Bosenberg, Marcus W.; Stern, David F.

    2015-01-01

    Targeting anti-apoptotic proteins can sensitize tumor cells to conventional chemotherapies or other targeted agents. Antagonizing the Inhibitor of Apoptosis Proteins (IAPs) with mimetics of the pro-apoptotic protein SMAC is one such approach. We used sensitization compound screening to uncover possible agents with the potential to further sensitize lung adenocarcinoma cells to the SMAC mimetic Debio 1143. Several compounds in combination with Debio 1143, including taxanes, topoisomerase inhibitors, and bromodomain inhibitors, super-additively inhibited growth and clonogenicity of lung adenocarcinoma cells. Co-treatment with Debio 1143 and the bromodomain inhibitor JQ1 suppresses the expression of c-IAP1, c-IAP2, and XIAP. Non-canonical NF-κB signaling is also activated following Debio 1143 treatment, and Debio 1143 induces the formation of the ripoptosome in Debio 1143-sensitive cell lines. Sensitivity to Debio 1143 and JQ1 co-treatment was associated with baseline caspase-8 expression. In vivo treatment of lung adenocarcinoma xenografts with Debio 1143 in combination with JQ1 or docetaxel reduced tumor volume more than either single agent alone. As Debio 1143-containing combinations effectively inhibited both in vitro and in vivo growth of lung adenocarcinoma cells, these data provide a rationale for Debio 1143 combinations currently being evaluated in ongoing clinical trials and suggest potential utility of other combinations identified here. PMID:26485762

  15. Fine-tuning the stimulation of MLL1 methyltransferase activity by a histone H3-based peptide mimetic

    SciTech Connect

    Avdic, Vanja; Zhang, Pamela; Lanouette, Sylvain

    2011-08-24

    The SET1 family of methyltransferases carries out the bulk of histone H3 Lys-4 methylation in vivo. One of the common features of this family is the regulation of their methyltransferase activity by a tripartite complex composed of WDR5, RbBP5, and Ash2L. To selectively probe the role of the SET1 family of methyltransferases, we have developed a library of histone H3 peptide mimetics and report herein the characterization of an N{alpha} acetylated form of histone H3 peptide (N{alpha}H3). Binding and inhibition studies reveal that the addition of an acetyl moiety to the N terminus of histone H3 significantly enhances its bindingmore » to WDR5 and prevents the stimulation of MLL1 methyltransferase activity by the WDR5-RbBP5-Ash2L complex. The crystal structure of N{alpha}H3 in complex with WDR5 reveals that a high-affinity hydrophobic pocket accommodates the binding of the acetyl moiety. These results provide the structural basis to control WDR5-RbBP5-Ash2L-MLL1 activity and a tool to manipulate stem cell differentiation programs.-Avdic, V., Zhang, P., Lanouette, S., Voronova, A., Skerjanc, I., Couture, J.-F. Fine-tuning the stimulation of MLL1 methyltransferase activity by a histone H3-based peptide mimetic.« less

  16. Anthraquinones from Morinda longissima and their insulin mimetic activities via AMP-activated protein kinase (AMPK) activation.

    PubMed

    Nguyen, Phi-Hung; Choi, Hong Seok; Ha, Thi Kim Quy; Seo, Ji Yeon; Yang, Jun-Li; Jung, Da-Woon; Williams, Darren R; Oh, Won-Keun

    2017-01-01

    AMP-activated protein kinase (AMPK) activators are known to increase energy metabolism and to reduce body weight, as well as to improve glucose uptake. During for searching AMPK activators, a new anthraquinone, modasima A (10), along with eighteen known analogues (1-9 and 11-19) were isolated from an ethanol extract of the roots of Morinda longissima Y. Z. Ruan (Rubiaceae). Using the fluorescent tagged glucose analogues, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-D-glucose (2-NBDG), insulin mimetics were screened with compounds 1-19 in 3T3-L1 adipocytes. Among them, compounds 2, 8 and 10 enhanced significantly glucose uptake into adipocytes and up-regulated the phosphorylated AMPK (Thr 172 ) whereas the glucose uptake enhancing activities of compounds 2, 8 and 10 were abrogated by treatment of compound C, an AMPK inhibitor. Taken together, these anthraquinones showed the potential action as insulin mimetic to improve glucose uptake via activation of AMPK. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. A botanically derived skin surface lipid mimetic based on the composition of healthy 22-year-old females.

    PubMed

    Addy, Jeff; Oliphant, Tiffany; Harper, Robert

    Skin surface lipids (SSLs) greatly affect the skin physiology and are thought to be involved in skin processes such as thermoregulation, bacterial colonization, and barrier function and maintenance. SSLs are primarily composed of fatty acids, triglycerides, cholesterol, steryl esters, wax esters, and squalene. The objective of this research was to evaluate and better understand the SSL composition and variation in an age- and sex-controlled population, and create an appropriate botanically derived mimetic. SSL samples taken from the foreheads of 59 healthy, 22-year-old females were analyzed by gas chromatography mass spectrometry (GC-MS). Using botanically derived raw materials from Macadamia integrifolia , Simmondsia chinensis , and Olea europaea , a mimetic was engineered via a series of esterification reactions and lipid components quantitated with GC-MS. The glyceride and wax ester components were produced by the interesterification of M. integrifolia and S. chinensis under specified conditions. The steryl ester component was produced by the esterification of the fatty acids of M. integrifolia and phytosterols under similar conditions. The following major classes of lipids were found and quantified by percent composition: glycerides, free fatty acids, squalene, wax esters, steryl esters, and cholesterol. The variability between subjects for each component was minimal; however, the greatest variation was seen for free fatty acids and cholesterol. Correlations among the components were calculated and found to be statistically or directionally significant with few exceptions. The esterification reactions of jojoba, macadamia, and tall oils, along with a precise addition of squalene derived from O. europaea , produced a suitable SSL mimetic. When applied to delipidized skin, the mimetic helped restore barrier function, increased skin hydration, and increased skin elasticity and firmness in aged skin. The present research indicates that, overall, the SSL composition

  18. Encoding physico-chemical cues in synthetic hydrogels by triple helix assembly of collagen mimetic peptides

    NASA Astrophysics Data System (ADS)

    Stahl, Patrick

    The ECM is a complex natural system evolved to promote proliferation and differentiation of cells during tissue development. In order to create synthetic biomaterials for studying cell-scaffold interactions and ultimately for engineering tissues, scientists strive to recapitulate many characteristics of ECM by developing hydrogels that contain mechanical cues and biochemical signals such as adhesion moieties and cell growth factors. While synthetic hydrogels bypass limitations of naturally-derived materials (e.g. transfer of pathogens), nature provides inspiration to enhance the functionality of synthetic hydrogels through biomimetic approaches. The collagen triple helix is the basis for the supramolecular structure of collagen in the ECM, and its adaptation in collagen mimetic peptides (CMPs) has provided hybridization mechanisms that can be employed in the formation and functionalization of synthetic hydrogels. The aim of this dissertation is to develop novel poly(ethylene glycol) (PEG)-based hydrogels that employ CMP triple helix assembly as a non-covalent yet target-specific tool to encode physical and chemical cues into the hydrogel with spatial control. We demonstrate that multi-arm PEG functionalized with CMPs form hydrogels supported by physical crosslinks mediated by CMP triple helix. Particle tracking microrheology shows that these physical crosslinks are sensitive to temperature as well as addition of exogenous CMPs that can disrupt crosslinks by competing for triple helix formation. This physical crosslink disruption enables the modulation of bulk hydrogel elasticity and the introduction of local stiffness gradients in PEG-CMP hydrogels. We also present photopolymerized PEG diacrylate (PEGDA) hydrogels displaying CMPs that can be further conjugated to CMPs with bioactive moieties via triple helix hybridization. Encoding these hydrogels with cell-adhesive CMPs induces cell spreading and proliferation. We further demonstrate generation of gradients and

  19. Development of electrospun bone-mimetic matrices for bone regenerative applications

    NASA Astrophysics Data System (ADS)

    Phipps, Matthew Christopher

    Although bone has a dramatic capacity for regeneration, certain injuries and procedures present defects that are unable to heal properly, requiring surgical intervention to induce and support osteoregeneration. Our research group has hypothesized that the development of a biodegradable material that mimics the natural composition and architecture of bone extracellular matrix has the potential to provide therapeutic benefit to these patients. Utilizing a process known as electrospinning, our lab has developed a bone-mimetic matrix (BMM) consisting of composite nanofibers of the mechanically sta-ble polymer polycaprolactone (PCL), and the natural bone matrix molecules type-I colla-gen and hydroxyapatite nanocrystals (HA). We herein show that BMMs supported great-er adhesion, proliferation, and integrin activation of mesenchymal stem cells (MSCs), the multipotent bone-progenitor cells within bone marrow and the periosteum, in comparison to electrospun PCL alone. These cellular responses, which are essential early steps in the process of bone regeneration, highlight the benefits of presenting cells with natural bone molecules. Subsequently, evaluation of new bone formation in a rat cortical tibia defect showed that BMMs are highly osteoconductive. However, these studies also revealed the inability of endogenous cells to migrate within electrospun matrices due to the inherently small pore sizes. To address this limitation, which will negatively impact the rate of scaf-fold-to-bone turnover and inhibit vascularization, sacrificial fibers were added to the ma-trix. The removal of these fibers after fabrication resulted in BMMs with larger pores, leading to increased infiltration of MSCs and endogenous bone cells. Lastly, we evaluat-ed the potential of our matrices to stimulate the recruitment of MSCs, a vital step in bone healing, through the sustained delivery of platelet derived growth factor-BB (PDGF-BB). BMMs were found to adsorb and subsequently release greater

  20. Bio-Mimetics of Disaster Anticipation—Learning Experience and Key-Challenges

    PubMed Central

    Tributsch, Helmut

    2013-01-01

    Simple Summary Starting from 1700 B.C. in the old world and up to recent times in China there is evidence of earthquake prediction based on unusual metrological phenomena and animal behavior. The review tries to explore the credibility and to pin down the nature of geophysical phenomena involved. It appears that the concept of ancient Greek philosophers in that a dry gas, pneuma is correlated with earthquakes, is relevant. It is not the cause of earthquakes, as originally thought, but may be an accompanying phenomenon and occasional precursor. This would explain unusual animal behavior as well as thermal anomalies detected from satellites. Abstract Anomalies in animal behavior and meteorological phenomena before major earthquakes have been reported throughout history. Bio-mimetics or bionics aims at learning disaster anticipation from animals. Since modern science is reluctant to address this problem an effort has been made to track down the knowledge available to ancient natural philosophers. Starting with an archaeologically documented human sacrifice around 1700 B.C. during the Minoan civilization immediately before a large earthquake, which killed the participants, earthquake prediction knowledge throughout antiquity is evaluated. Major practical experience with this phenomenon has been gained from a Chinese earthquake prediction initiative nearly half a century ago. Some quakes, like that of Haicheng, were recognized in advance. However, the destructive Tangshan earthquake was not predicted, which was interpreted as an inherent failure of prediction based on animal phenomena. This is contradicted on the basis of reliable Chinese documentation provided by the responsible earthquake study commission. The Tangshan earthquake was preceded by more than 2,000 reported animal anomalies, some of which were of very dramatic nature. They are discussed here. Any physical phenomenon, which may cause animal unrest, must involve energy turnover before the main earthquake

  1. Combinational Spinal GAD65 Gene Delivery and Systemic GABA-Mimetic Treatment for Modulation of Spasticity

    PubMed Central

    Kakinohana, Osamu; Hefferan, Michael P.; Miyanohara, Atsushi; Nejime, Tetsuya; Marsala, Silvia; Juhas, Stefan; Juhasova, Jana; Motlik, Jan; Kucharova, Karolina; Strnadel, Jan; Platoshyn, Oleksandr; Lazar, Peter; Galik, Jan; Vinay, Laurent; Marsala, Martin

    2012-01-01

    Background Loss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABAB receptor agonist), while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments. Methods/Principal Findings Adult Sprague-Dawley (SD) rats were exposed to transient spinal ischemia (10 min) to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs) targeting ventral α-motoneuronal pools. At 2–3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle) and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only) had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene. Conclusions/Significance These data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can represent a novel

  2. RGD and BMP-2 mimetic peptide crosstalk enhances osteogenic commitment of human bone marrow stem cells.

    PubMed

    Bilem, I; Chevallier, P; Plawinski, L; Sone, E D; Durrieu, M C; Laroche, G

    2016-05-01

    Human bone marrow mesenchymal stem cells (hBMSCs) commitment and differentiation are dictated by bioactive molecules sequestered within their Extra Cellular Matrix (ECM). One common approach to mimic the physiological environment is to functionalize biomaterial surfaces with ECM-derived peptides able to recruit stem cells and trigger their linage-specific differentiation. The objective of this work was to investigate the effect of RGD and BMP-2 ligands crosstalk and density on the extent of hBMSCs osteogenic commitment, without recourse to differentiation medium. RGD peptide promotes cell adhesion via cell transmembrane integrin receptors, while BMP-2 peptide, corresponding to residues 73-92 of Bone Morphogenetic Protein-2, was shown to induce hBMSCs osteoblast differentiation. The immobilization of peptides on aminated glass was ascertained by X-ray Photoelectron Spectroscopy (XPS), the density of grafted peptides was quantified by fluorescence microscopy and the surface roughness was evaluated using Atomic Force Microscopy (AFM). The osteogenic commitment of hBMSCs cultured on RGD and/or BMP-2 surfaces was characterized by immunohistochemistry using STRO-1 as specific stem cells marker and Runx-2 as an earlier osteogenic marker. Biological results showed that the osteogenic commitment of hBMSCs was enhanced on bifunctionalized surfaces as compared to surfaces containing BMP-2, while on RGD surfaces cells mainly preserved their stemness character. These results demonstrated that RGD and BMP-2 mimetic peptides act synergistically to enhance hBMSCs osteogenesis without supplementing the media with osteogenic factors. These findings contribute to the development of biomimetic materials, allowing a deeper understanding of signaling pathways that govern the transition of stem cells towards the osteoblastic lineage. For a long time, scientists thought that the differentiation of Mesenchymal Stem Cells (MSCs) into bone cells was dictated by growth factors. This

  3. Thioredoxin-Mimetic-Peptides Protect Cognitive Function after Mild Traumatic Brain Injury (mTBI)

    PubMed Central

    Baratz-Goldstein, Renana; Deselms, Hanna; Heim, Leore Raphael; Khomski, Lena; Hoffer, Barry J.

    2016-01-01

    Mild traumatic brain injury (mTBI) is recognized as a common injury among children, sportsmen, and elderly population. mTBI lacks visible objective structural brain damage but patients frequently suffer from long-lasting cognitive, behavioral and emotional difficulties associated with biochemical and cellular changes. Currently there is no effective treatment for patients with mTBI. The thioredoxin reductase/thioredoxin pathway (TrxR/Trx1) has both anti-inflammatory and anti-oxidative properties. If the system is compromised, Trx1 remains oxidized and triggers cell death via an ASK1-Trx1 signal transduction mechanism. We previously showed tri and tetra peptides which were derived from the canonical -CxxC- motif of the Trx1-active site, called thioredoxin mimetic (TXM) peptides, reversed inflammatory and oxidative stress damage mimicking Trx1 activity. Here, TXM-peptides were examined for protecting cognitive function following weight drop closed-head injury in a mouse model of mTBI. TXM-CB3 (AcCys-Pro-CysNH2), TXM-CB13 (DY-70; AcCys-Met-Lys-CysNH2) or AD4 (ACysNH2) were administered at 50 mg/kg, 60 min after injury and cognitive performance was monitored by the novel-object-recognition and Y-maze tests. Behavioral deficits subsequent to mTBI injury were reversed by a single dose of TXM-CB3, TXM-CB13 and, to a lesser extent, by AD4. TXM-CB13 similar to TXM-CB3 and AD4 reversed oxidative stress-induced phosphorylation of mitogen-activated kinases, p38MAPK and c-Jun N-terminal kinase, (JNK) in human neuronal SH-SY5Y cells. We conclude that significantly improved cognitive behavior post mTBI by the TXM-peptides could result from anti-apoptotic, and/or anti-inflammatory activities. Future preclinical studies are required to establish the TXM-peptides as potential therapeutic drugs for brain injuries. PMID:27285176

  4. Microfluidic paper-based device for colorimetric determination of glucose based on a metal-organic framework acting as peroxidase mimetic.

    PubMed

    Ortiz-Gómez, Inmaculada; Salinas-Castillo, Alfonso; García, Amalia García; Álvarez-Bermejo, José Antonio; de Orbe-Payá, Ignacio; Rodríguez-Diéguez, Antonio; Capitán-Vallvey, Luis Fermín

    2017-12-13

    This work presents a microfluidic paper-based analytical device (μPAD) for glucose determination using a supported metal-organic framework (MOF) acting as a peroxidase mimic. The catalytic action of glucose oxidase (GOx) on glucose causes the formation of H 2 O 2 , and the MOF causes the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H 2 O 2 to form a blue-green product with an absorption peak at 650 nm in the detection zone. A digital camera and the iOS feature of a smartphone are used for the quantitation of glucose with the S coordinate of the HSV color space as the analytical parameter. Different factors such as the concentration of TMB, GOx and MOF, pH and buffer, sample volume, reaction time and reagent position in the μPAD were optimized. Under optimal conditions, the value for the S coordinate increases linearly up to 150 μmol·L -1 glucose concentrations, with a 2.5 μmol·L -1 detection limit. The μPAD remains stable for 21 days under conventional storage conditions. Such an enzyme mimetic-based assay to glucose determination using Fe-MIL-101 MOF implemented in a microfluidic paper-based device possesses advantages over enzyme-based assays in terms of costs, durability and stability compared to other existing glucose determination methods. The procedure was applied to the determination of glucose in (spiked) serum and urine. Graphical abstract Schematic representation of microfluidic paper-based analytical device using metal-organic framework as a peroxidase mimic for colorimetric glucose detection with digital camera or smartphone and iOS app readout.

  5. The enhancement of TXA2receptors-mediated contractile response in intrarenal artery dysfunction in type 2 diabetic mice.

    PubMed

    Kuang, Su-Juan; Qian, Jie-Sheng; Yang, Hui; Rao, Fang; Chen, Xiao-Yan; Zhang, Meng-Zhen; Shan, Zhi-Xin; Lin, Qiu-Xiong; Xue, Yu-Mei; Wu, Shu-Lin; Jiang, Li; Chen, Chun-Bo; Deng, Chun-Yu

    2017-06-15

    Thromboxane A 2 (TXA 2 ) has been implicated in the pathogenesis of diabetic vascular complications, although the underlying mechanism remains unclear. The present study investigated the alterations in TXA 2 receptor signal transduction in type 2 diabetic renal arteries. The contraction of renal arterial rings in control (db/m+) mice and type 2 diabetic (db/db) mice was measured by a Multi Myograph System. Intracellular calcium concentration ([Ca 2+ ] i ) in vascular smooth muscle cells was measured by Fluo-4/AM dye and confocal laser scanning microscopy. Quantitative real-time PCR and Western blot analysis were used to determine gene and protein expression levels, respectively. A stable TXA 2 mimic U46619 caused markedly stronger dose-dependent contractions in the renal arteries of db/db mice than in those of db/m + mice. This response was completely blocked by a TXA 2 receptor antagonist GR32191 and significantly inhibited by U73122. U46619-induced vasoconstriction was increased in the presence of nifedipine in db/db mice compared with that in db/m + mice, whereas the response to U46619 did not differ between the two groups in the presence of SKF96365. Sarcoplasmic reticulum Ca 2+ release-mediated and CaCl 2 -induced contractions did not differ between the two groups. In db/db mice, store-operated Ca 2+ (SOC) entry-mediated contraction in the renal arteries and SOC entry-mediated Ca 2+ influx in smooth muscle cells were significantly increased. And the gene and protein expressions of TXA 2 receptors, Orai1 and Stim1 were upregulated in the diabetic renal arteries. Therefore the enhancement of U46619-induced contraction was mediated by the upregulation of TXA 2 receptors and downstream signaling in the diabetic renal arteries. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Endothelin‐1 shifts the mediator of bradykinin‐induced relaxation from NO to H2O2 in resistance arteries from patients with cardiovascular disease

    PubMed Central

    Leurgans, Thomas M; Bloksgaard, Maria; Brewer, Jonathan R; Bagatolli, Luis A; Fredgart, Maise H; Rosenstand, Kristoffer; Hansen, Maria L; Rasmussen, Lars M; Irmukhamedov, Akhmadjon

    2016-01-01

    Background and Purpose We tested the hypothesis that in resistance arteries from cardiovascular disease (CVD) patients, effects of an endothelium‐dependent vasodilator depend on the contractile stimulus. Experimental Approach Arteries dissected from parietal pericardium of cardiothoracic surgery patients were studied by myography and imaging techniques. Segments were sub‐maximally contracted by K+, the TxA2 analogue U46619 or endothelin‐1 (ET‐1). Key Results Relaxing effects of Na‐nitroprusside were comparable, but those of bradykinin (BK) were bigger in the presence of ET‐1 compared with K+ or U46619. BK‐induced relaxation was (i) abolished by L‐NAME in K+‐contracted arteries, (ii) partly inhibited by L‐NAME in the presence of U46619 and (iii) not altered by indomethacin, L‐NAME plus inhibitors of small and intermediate conductance calcium‐activated K+ channels, but attenuated by catalase, in ET‐1‐contracted arteries. This catalase‐sensitive relaxation was unaffected by inhibitors of NADPH oxidases or allopurinol. Exogenous H2O2 caused a larger relaxation of ET‐1‐induced contractions than those evoked by K+ or U46619 in the presence of inhibitors of other endothelium‐derived relaxing factors. Catalase‐sensitive staining of cellular ROS with CellROX Deep Red was significantly increased in the presence of both 1 μM BK and 2 nM ET‐1 but not either peptide alone. Conclusions and Implications In resistance arteries from patients with CVD, exogenous ET‐1 shifts the mediator of relaxing responses to the endothelium‐dependent vasodilator BK from NO to H2O2 and neither NADPH oxidases, xanthine oxidase nor NOS appear to be involved in this effect. This might have consequences for endothelial dysfunction in conditions where intra‐arterial levels of ET‐1 are enhanced. PMID:26914408

  7. Smac mimetic enables the anticancer action of BCG-stimulated neutrophils through TNF-α but not through TRAIL and FasL

    PubMed Central

    Jinesh G., Goodwin; Chunduru, Srinivas; Kamat, Ashish M.

    2012-01-01

    BCG, the current gold standard immunotherapy for bladder cancer, exerts its activity via recruitment of neutrophils to the tumor microenvironment. Many patients do not respond to BCG therapy, indicating the need to understand the mechanism of action of BCG-stimulated neutrophils and to identify ways to overcome resistance to BCG therapy. Using isolated human neutrophils stimulated with BCG, we found that TNF-α is the key mediator secreted by BCG-stimulated neutrophils. RT4v6 human bladder cancer cells, which express TNFR1, CD95/Fas, CD95 ligand/FasL, DR4, and DR5, were resistant to BCG-stimulated neutrophil conditioned medium but effectively killed by the combination of conditioned medium and Smac mimetic. rhTNF-α and rhFasL, but not rhTRAIL, in combination with Smac mimetic, generated signature molecular events similar to those produced by BCG-stimulated neutrophils in combination with Smac mimetic. However, experiments using neutralizing antibodies to these death ligands showed that TNF-α secreted from BCG-stimulated neutrophils was the key mediator of anticancer action. These findings explain the mechanism of action of BCG and identified Smac mimetics as potential combination therapeutic agents for bladder cancer. PMID:22517918

  8. Davalintide (AC2307), a Novel Amylin Mimetic Peptide: Enhanced Pharmacological Properties over Native Amylin to Reduce Food Intake and Body Weight

    USDA-ARS?s Scientific Manuscript database

    Objective: These studies describe the in vivo metabolic actions of the novel amylin mimetic peptide davalintide (AC2307) in rodents, and compare these effects to those of the native peptide. Research Design and Methods: The anti-obesity effects of davalintide were examined following intraperitoneal ...

  9. Synthesis, molecular docking and biological evaluation as HDAC inhibitors of cyclopeptide mimetics by a tandem three-component reaction and intramolecular [3+2] cycloaddition.

    PubMed

    Pirali, Tracey; Faccio, Valeria; Mossetti, Riccardo; Grolla, Ambra A; Di Micco, Simone; Bifulco, Giuseppe; Genazzani, Armando A; Tron, Gian Cesare

    2010-02-01

    Novel macrocyclic peptide mimetics have been synthesized by exploiting a three-component reaction and an azide-alkyne [3 + 2] cycloaddition. The prepared compounds were screened as HDAC inhibitors allowing us to identify a new compound with promising biological activity. In order to rationalize the biological results, computational studies have also been performed.

  10. Effect of fat level on the perception of five flavor chemicals in ice cream with or without fat mimetics by using a descriptive test.

    PubMed

    Liou, B K; Grün, I U

    2007-10-01

    Fat mimetics are commonly used in the manufacture of low-fat and fat-free ice creams. However, the use of fat mimetics affects flavor and texture characteristics of ice cream, which results in decreased overall acceptability by consumers. The initial objective of this study was to investigate the release behavior of 5 strawberry flavor compounds in ice creams with Simplesse((R)), Litesse((R)), and Litesse((R))/Simplesse((R)) mixes using descriptive analysis. Fat mimetics and flavor formulation significantly influenced the perception of Furaneoltrade mark (cooked sugar flavor), alpha-ionone (violet flavor), and gamma-undecalactone (peach flavor), but there was no interaction between ice cream type and flavor formulation for the 3 flavors. Furaneol and ethyl-3-methyl-3-phenylglycidate (candy flavor) were perceived more strongly in full-fat ice cream, while cis-3-hexen-1-ol (grassy flavor), alpha-ionone, and gamma-undecalactone were perceived more strongly in low-fat ice cream. Ice creams with Simplesse and full-fat ice cream had similar sensory characteristics, while ice creams with Litesse were similar to low-fat ice creams in flavor characteristics, and ice creams with Litesse/Simplesse mixes were closer in flavor profile to low-fat ice cream but had similar texture properties to those of full-fat ice cream. Simplesse was found to be a better fat mimetic for duplicating the flavor profiles and mouthfeel of full-fat ice cream.

  11. The effect of collagen I mimetic peptides on mesenchymal stem cell adhesion and differentiation, and on bone formation at hydroxyapatite surfaces

    PubMed Central

    Hennessy, KM; Pollot, BE; Clem, WC; Phipps, MC; Sawyer, AA; Culpepper, K; Bellis, SL

    2013-01-01

    Integrin-binding peptides increase cell adhesion to naive hydroxyapatite (HA), however, in the body, HA becomes rapidly modified by protein adsorption. Previously we reported that, when combined with an adsorbed protein layer, RGD peptides interfered with cell adhesion to HA. In the current study we evaluated mesenchymal stem cell (MSC) interactions with HA disks coated with the collagen-mimetic peptides, DGEA, P15 and GFOGER. MSCs adhered equally well to disks coated with DGEA, P15, or collagen I, and all three substrates, but not GFOGER, supported greater cell adhesion than uncoated HA. When peptide-coated disks were overcoated with proteins from serum or the tibial microenvironment, collagen mimetics did not inhibit MSC adhesion, as was observed with RGD, however neither did they enhance adhesion. Given that activation of collagen-selective integrins stimulates osteoblastic differentiation, we monitored osteocalcin secretion and alkaline phosphatase activity from MSCs adherent to DGEA or P15-coated disks. Both of these osteoblastic markers were upregulated by DGEA and P15, in the presence and absence of differentiation-inducing media. Finally, bone formation on HA tibial implants was increased by the collagen-mimetics. Collectively these results suggest that collagen-mimetic peptides improve osseointegration of HA, most probably by stimulating osteoblastic differentiation, rather than adhesion, of MSCs. PMID:19157536

  12. Use of cloneable peptide-MBP fusion protein as a mimetic coating antigen in the standardized immunoassay for mycotoxin ochratoxin A.

    PubMed

    Xu, Yang; He, Zhenyun; He, Qinghua; Qiu, Yulou; Chen, Bo; Chen, Jing; Liu, Xing

    2014-09-03

    The quality of mycotoxin conjugates is essential to the development of reliability of immunoassays for mycotoxins. However, conventional mycotoxin conjugates are usually synthesized by chemical methods, which are harmful to the environment and yield unwanted cross-reactions. In this study, using ochratoxin A (OTA) as a model system, a selected OTA mimotope (phage-displayed peptide) that specifically binds to anti-OTA antibody was expressed as soluble and monovalent fusions to maltose binding protein (MBP). These prepared fusion proteins can serve as a mimetic coating antigen in both a quantitative chemiluminescent enzyme-linked immunoassay (CLEIA) and a qualitative dot immunoassay for OTA. One of the prepared mimetic coating antigen (L12-206-MBP)-based CLEIAs exhibited a half-inhibition concentration (IC50) of 0.82 ng/mL and a working range of 0.30-2.17 ng/mL, which resemble those of the conventional OTA-OVA conjugate-based immunoassay. The dot immunoassay developed with both the OTA-OVA conjugate and the mimetics showed identical visual cutoff values of 5 ng/mL. The mimetic coating antigen proposed here is an OTA-free product and can be prepared reproducibly as a homogeneous product and facilitates standardization of immunoassays for the mycotoxin OTA.

  13. Comparison of the involvement of protein kinase C in agonist-induced contractions in mouse aorta and corpus cavernosum.

    PubMed

    Jin, Liming; Teixeira, Cleber E; Webb, R Clinton; Leite, Romulo

    2008-08-20

    Protein kinase C (PKC) is involved in the regulation of vascular smooth muscle contraction. However, the role of PKC in erectile function is poorly understood. This study investigated whether PKC mediates agonist-induced contractions in mouse penile tissue (corpora cavernosa). We also compared the effects of PKC activators and inhibitors on contractile responses in mouse corpus cavernosum with those in mouse aorta. Aortic rings and corpus cavernosal strips from C57BL/6J mice were mounted in the organ bath for isometric tension recording. Our data showed that a PKC(alpha/beta) selective inhibitor, G(ö)6976 (10 microM), inhibited phenylephrine and 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619, a thromboxane mimetic)-induced contractions in mouse aorta, reducing the maximum contraction by 94% and 17%, respectively. A non-selective PKC inhibitor, chelerythrine (30 microM), also significantly reduced phenylephrine- and U46619-induced maximum contractions in mouse aorta. However, G(ö)6976 and chelerythrine had no significant effects on phenylephrine- and U46619-induced contractions in corpus cavernosum. Furthermore, a PKC activator, phorbol-12,13-dibutyrate (0.1 microM), significantly increased contractions in aorta (208+/-14% of KCl-induced maximum contraction) but failed to cause contractions in corpus cavernosum at 1 and 10 microM. Western blot analysis data suggested that protein expression of PKC was similar in aorta and corpus cavernosum. Taken together, our data indicate that PKC does not have a significant role in agonist-induced contractions in mouse corpus cavernosum, whereas it mediates the contractile response to agonists in the aorta.

  14. The selective carotid arterial vasoconstrictor action of GR43175 in anaesthetized dogs.

    PubMed Central

    Feniuk, W.; Humphrey, P. P.; Perren, M. J.

    1989-01-01

    1. GR43175 is a highly selective agonist at 5-HT1-like receptors in the dog saphenous vein. This study describes the haemodynamic effects of GR43175 in barbitone-anaesthetized dogs. 2. GR43175 (1-1000 micrograms kg-1, i.v.) produced dose-dependent decreases in carotid arterial blood flow with little or no change in arterial blood pressure. The decrease in blood flow was associated with an increase in carotid arterial vascular resistance. In preliminary studies, the dose of GR43175 producing 50% of the maximum carotid vasoconstrictor response was 39 +/- 8 micrograms kg-1, i.v. 3. In comparative regional haemodynamic studies, GR43175 (1-1000 micrograms kg-1, i.v.) had little effect on total peripheral resistance or resistance in the mesenteric, vertebral and coronary arterial vascular beds. Low doses of GR43175 decreased, whilst high doses (100 micrograms kg-1, i.v. and above) increased femoral arterial vascular resistance. GR43175 (1-1000 micrograms kg-1, i.v.) had no effect on respiratory inflation pressure. In doses of 100 micrograms kg-1 i.v. and above, GR43175 caused small decreases in heart rate. 4. The carotid arterial vasoconstrictor action of GR43175 was resistant to antagonism by the 5-HT2 receptor, 5-HT3 receptor and alpha-adrenoceptor blocking drugs, ketanserin, MDL72222 and phentolamine respectively, but could be antagonized by the non-selective 5-HT1-like receptor blocking drug methiothepin. Methiothepin had no effect on the carotid vasoconstrictor action of the thromboxane A2 mimetic, U46619. 5. The results demonstrate that GR43175 produces a selective vasoconstriction in the carotid arterial circulation of anaesthetized dogs via activation of 5-HT1-like receptors, which appear similar to those mediating contraction of the dog isolated saphenous vein. PMID:2538184

  15. Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers.

    PubMed

    Lueck, Sonja C; Russ, Annika C; Botzenhardt, Ursula; Schlenk, Richard F; Zobel, Kerry; Deshayes, Kurt; Vucic, Domagoj; Döhner, Hartmut; Döhner, Konstanze; Fulda, Simone; Bullinger, Lars

    2016-08-02

    Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. Notably, 69% of ara-C-resistant samples show a good to fair response to BV6. Furthermore, combination treatment with ara-C and BV6 exerts additive effects in most samples. Whole-genome gene expression profiling identifies cell death, TNFR1 and NF-κB signaling among the top pathways that are activated by BV6 in BV6-sensitive, but not in BV6-resistant cases. Furthermore, sensitivity of primary AML blasts to BV6 correlates with significantly elevated expression levels of TNF and lower levels of XIAP in diagnostic samples, as well as with NPM1 mutation. In a large set of primary AML samples, these data provide novel insights into factors regulating Smac mimetic response in AML and have important implications for the development of Smac mimetic-based therapies and related diagnostics in AML.

  16. Chemistry and insulin-mimetic properties of bis(acetylacetonate)oxovanadium(IV) and derivatives.

    PubMed

    Amin, S S; Cryer, K; Zhang, B; Dutta, S K; Eaton, S S; Anderson, O P; Miller, S M; Reul, B A; Brichard, S M; Crans, D C

    2000-02-07

    The syntheses and the solid state structural and spectroscopic solution characterizations of VO(Me-acac)2 and VO(Et-acac)2 (where Me-acac is 3-methyl-2,4-pentanedionato and Et-acac is 3-ethyl-2,4-pentanedionato) have been conducted since both VO(acac)2 and VO(Et-acac)2 have long-term in vivo insulin-mimetic effects in streptozotocin-induced diabetic Wistar rats. X-ray structural characterizations of VO(Me-acac)2 and VO(Et-acac)2 show that both contain five-coordinate vanadium similar to the parent VO(acac)2. The unit cells for VO(Et-acac)2 and VO(Me-acac)2 are both triclinic, P1, with a = 9.29970(10) A, b = 13.6117(2) A, c = 13.6642(2) A, alpha = 94.1770(10) degrees, beta = 106.4770(10) degrees, gamma = 106.6350(10) degrees for VO(Et-acac)2 and a = 7.72969(4) A, b = 8.1856(5) A, c = 11.9029(6) A, alpha = 79.927(2) degrees, beta = 73.988(2)degrees, gamma = 65.1790(10)degrees for VO(Me-acac)2. The total concentration of EPR-observable vanadium(IV) species for VO(acac)2 and derivatives in water solution at 20 degreesC was determined by double integration of the EPR spectra and apportioned between individual species on the basis of computer simulations of the spectra. Three species were observed, and the concentrations were found to be time, pH, temperature, and salt dependent. The three complexes are assigned as the trans-VO(acac)2.H2O adduct, cis-VO(acac)2.H2O adduct, and a hydrolysis product containing one vanadium atom and one R-acac- group. The reaction rate for conversion of species was slower for VO(acac)2 than for VO(malto)2, VO(Et-acac)2, and VO(Me-acac)2; however, in aqueous solution the rates for all of these species are slow compared to those of other vanadium species. The concentration of vanadium(V) species was determined by 51V NMR. The visible spectra were time dependent, consistent with the changes in species concentrations that were observed in the EPR and NMR spectra. EPR and visible spectroscopic studies of solutions prepared as for administration

  17. Conformational assembly and biological properties of collagen mimetic peptides and their thermally responsive polymer conjugates

    NASA Astrophysics Data System (ADS)

    Krishna, Ohm Divyam

    2011-12-01

    Collagens are one of the most abundant proteins found in body tissues and organs, endowing structural integrity, mechanical strength, and multiple biological functions. Destabilized collagen inside human body leads to various degenerative diseases (ex. osteoarthritis) and ageing. This has continued to motivate the design of synthetic peptides and bio-synthetic polypeptides to closely mimic the native collagens in terms of triple helix structure and stability, potential for higher order assembly, and biological properties. However, the widespread application of de novo collagens has been limited in part by the need for hydroxylated proline in the formation of stable triple helical structures. To address this continued need, a hydroxyproline-free, thermally stable collagen-mimetic peptide (CLP-Cys) was rationally designed via the incorporation of electrostatically stabilized amino acid triplets. CLP-Cys was synthesized via solid phase peptide synthesis. The formation and stability of the triple helical structure were indicated via circular dichroism (CD) experiments and confirmed via differential scanning calorimetry (DSC) results. CLP-Cys also self-assembled into nano-rods and micro-fibrils, as evidenced via a combination of dynamic light scattering and transmission electron microscopy. Given the high thermal stability and its propensity for higher-order assembly, CLP-Cys was further functionalized at both the ends with a thermally responsive polymer, poly(diethylene glycol methyl ether methacrylate), (PDEGMEMA) to synthesize a biohybrid triblock copolymer. The CD results indicated that the triple helical form is retained, the thermal unfolding is sustained and helix to coil transition is reversible in the triblock hybrid context. The LCST of PDEGMEMA homopolymer (26 °C) is increased (to 35 °C) upon conjugation to the hydrophilic collagen peptide domain. Further, a combination of static light scattering, Cryo-SEM, TEM and confocal microscopy elucidated that the

  18. A novel insulin mimetic vanadium-flavonol complex: synthesis, characterization and in vivo evaluation in STZ-induced rats.

    PubMed

    Pillai, Subramanian Iyyam; Subramanian, Sorimuthu Pillai; Kandaswamy, Muthusamy

    2013-05-01

    Since 1985, when Heyliger et al., first demonstrated a serendipitous discovery that oral administration of 0.8 mg/ml of sodium orthovanadate in drinking water to streptozotocin-induced diabetic rats resulted in normoglycemia, numerous extensive studies have been pursued on the anti-diabetic and insulinomimetic actions of vanadium. The acceptance of vanadium compounds as promising therapeutic antidiabetic agents has been slowed due to the concern for chronic toxicity associated with vanadium accumulation. In order to circumvent the toxic effects of vanadium, we have taken up a combinational approach wherein a novel vanadium-flavonol complex was synthesized, characterized and its toxic as well as insulin mimetic potential was evaluated in STZ-induced experimental diabetes in rats. The results indicate that the complex is non-toxic and possess anti-diabetic activity. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  19. Peroxide(s) of vanadium: a novel and potent insulin-mimetic agent which activates the insulin receptor kinase.

    PubMed

    Kadota, S; Fantus, I G; Deragon, G; Guyda, H J; Hersh, B; Posner, B I

    1987-08-31

    The actions of insulin, vanadate (V) and hydrogen peroxide (H2O2) on IGF-II binding and insulin receptor tyrosine kinase activity were studied in rat adipocytes. Incubating adipocytes with a combination of V plus H2O2 resulted in a potent synergistic effect on both the increase in IGF-II binding and the activation of the insulin receptor kinase. Catalase, which removes H2O2, abolished this synergism if added at the time of mixing of V plus H2O2 but not if added 10 min. later, suggesting that the formation of peroxide(s) of vanadate generated a potent insulin mimicker. The data support a critical role for the insulin receptor kinase in insulin action. The novel insulin-mimetic compound, a presumed peroxide of vanadate, could prove useful for investigating insulin action and may be valuable for treating insulin resistance.

  20. TREATMENT OF DIABETES MELLITUS IN A GOLDEN LION TAMARIN (LEONTOPITHECUS ROSALIA) WITH THE GLUCAGON-LIKE PEPTIDE-1 MIMETIC EXENATIDE.

    PubMed

    Johnson, James G; Langan, Jennifer N; Gilor, Chen

    2016-09-01

    An 8-yr-old male golden lion tamarin ( Leontopithecus rosalia ) was diagnosed with diabetes mellitus based on hyperglycemia and persistent glycosuria. Initial treatment consisted of the oral antihyperglycemic medications glipizide and metformin that resulted in decreased blood glucose concentrations; however, marked glycosuria persisted. Insufficient improvement on oral antihyperglycemic therapy and poor feasibility of daily subcutaneous insulin therapy led to an investigation into an alternative therapy with extended-release exenatide, a glucagon-like peptide-1 (GLP-1) mimetic, at a dosage of 0.13 mg/kg subcutaneously once per month. Following treatment with exenatide, the persistent glycosuria resolved, the animal maintained normal blood glucose concentrations, and had lower serum fructosamine concentrations compared to pretreatment levels. Based on these findings, extended-release exenatide could be considered as a therapeutic option in nonhuman primates with diabetes mellitus that do not respond to oral antihyperglycemics and in which daily subcutaneous insulin is not feasible.

  1. Discovering the enzyme mimetic activity of metal-organic framework (MOF) for label-free and colorimetric sensing of biomolecules.

    PubMed

    Wang, Ying; Zhu, Yingjing; Binyam, Atsebeha; Liu, Misha; Wu, Yinan; Li, Fengting

    2016-12-15

    A label-free sensing strategy based on the enzyme-mimicking activity of MOF was demonstrated for colorimetric detection of biomolecules. Firstly obvious blue color was observed due to the high efficiency of peroxidase-like catalytic activity of Fe-MIL-88A (an ion-based MOF material) toward 3,3',5,5'-tetramethylbenzidine (TMB). Then in the presence of target biomolecule and corresponding aptamer, the mimetic activity of Fe-MIL-88A can be strongly inhibited and used directly to realize the colorimetric detection. On the basis of the interesting findings, we designed a straightforward, label-free and sensitive colorimetric method for biomolecule detection by using the enzyme mimetic property of MOF coupling with molecular recognition element. Compared with the existed publications, our work breaks the routine way by setting up an inorganic-organic MOF-aptamer hybrid platform for colorimetric determination of biomolecules, expanding the targets scope from H2O2 or glucose to biomolecules. As a proof of concept, thrombin and thrombin aptamer was used as a model analyte. The limit of detection of 10nM can be achieved with naked eyes and ultrahigh selectivity of thrombin toward numerous interfering substances with 10-fold concentration was demonstrated significantly. Of note, the method was further applied for the detection of thrombin in human serum samples, showing the results in agreement with those values obtained in an immobilization buffer by the colorimetric method. This inorganic-organic MOF-aptamer sensing strategy may in principle be universally applicable for the detection of a range of environmental or biomedical molecules of interests. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Mimetic muscles and emotions: Hans Memling's fifteenth century masterpiece, "Last judgment," as a study for aesthetic surgery.

    PubMed

    Jankau, Jerzy; Grzybiak, Marek

    2002-01-01

    As the most recognizable part of the body, the face has always interested, not only artists, but doctors as well. Each has had their own perception of facial beauty. The task for plastic and aesthetic surgery regarding the face is to reconstruct, not only traumatic lesions, but also to prevent the effects of facial tissue aging. It is also important to preserve the aesthetic values of the face in different emotional conditions. Those conditions are partially represented by mimetic or facial muscles. One might suggest that the perception of human beings portrayed by the artists could be very helpful in the realm of plastic and aesthetic surgery. Take, for example, Hans Memling, a fifteenth century Flemish artist whose masterpiece "Last Judgment" is exhibited at Gdańsk National Museum in Poland. The fortunate individuals on the left side of the painting are queuing at heaven's gate to receive their reward. Their faces are smooth with smiles, displaying blessings and happiness. The right-hand side of the painting exemplifies the expression of fear and the drama of the situation. These sinners have been damned and sentenced to hell by evil creatures. The fear, pain, and tragedy of condemnation fill their faces. For plastic and cosmetic surgeons, studying the works of great artists has not been as valuable as using the emotionless and intangible figures of an anatomy book. Undoubtedly, the only useful paintings and sculptures are those that are full of expression with the face displaying a plethora of emotions. In all surgical approaches where mimetic muscles are concerned, one has to remember and be conscious of the fact that the face is a very significant part of our body.

  3. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes.

    PubMed

    Fulcher, G; Matthews, D R; Perkovic, V; de Zeeuw, D; Mahaffey, K W; Mathieu, C; Woo, V; Wysham, C; Capuano, G; Desai, M; Shaw, W; Vercruysse, F; Meininger, G; Neal, B

    2016-01-01

    To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist]. CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18. Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues. In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition. © 2015 John Wiley & Sons Ltd.

  4. Therapy of prostate cancer using a novel cancer terminator virus and a small molecule BH-3 mimetic.

    PubMed

    Sarkar, Siddik; Quinn, Bridget A; Shen, Xue-Ning; Dash, Rupesh; Das, Swadesh K; Emdad, Luni; Klibanov, Alexander L; Wang, Xiang-Yang; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

    2015-05-10

    Despite recent advances, treatment options for advanced prostate cancer (CaP) remain limited. We are pioneering approaches to treat advanced CaP that employ conditionally replication-competent oncolytic adenoviruses that simultaneously produce a systemically active cancer-specific therapeutic cytokine, mda-7/IL-24, Cancer Terminator Viruses (CTV). A truncated version of the CCN1/CYR61 gene promoter, tCCN1-Prom, was more active than progression elevated gene-3 promoter (PEG-Prom) in regulating transformation-selective transgene expression in CaP and oncogene-transformed rat embryo cells. Accordingly, we developed a new CTV, Ad.tCCN1-CTV-m7, which displayed dose-dependent killing of CaP without harming normal prostate epithelial cells in vitro with significant anti-cancer activity in vivo in both nude mouse CaP xenograft and transgenic Hi-Myc mice (using ultrasound-targeted microbubble (MB)-destruction, UTMD, with decorated MBs). Resistance to mda-7/IL-24-induced cell death correlated with overexpression of Bcl-2 family proteins. Inhibiting Mcl-1 using an enhanced BH3 mimetic, BI-97D6, sensitized CaP cell lines to mda-7/IL-24-induced apoptosis. Combining BI-97D6 with Ads expressing mda-7/IL-24 promoted ER stress, decreased anti-apoptotic Mcl-1 expression and enhanced mda-7/IL-24 expression through mRNA stabilization selectively in CaP cells. In Hi-myc mice, the combination induced enhanced apoptosis and tumor growth suppression. These studies highlight therapeutic efficacy of combining a BH3 mimetic with a novel CTV, supporting potential clinical applications for treating advanced CaP.

  5. Evaluation of insulin-mimetic activities of vanadyl and zinc(II) complexes from the viewpoint of heterocyclic bidentate ligands.

    PubMed

    Katoh, Akira; Matsumura, Yuriko; Yoshikawa, Yutaka; Yasui, Hiroyuki; Sakurai, Hiromu

    2009-04-01

    Vanadyl sulfate (VOSO(4)) has been clinically tested in diabetic patients since 1995. Oral administrations of VOSO(4) improved the type 2 diabetic state with respect to plasma glucose, HbA(1c), and fructosamine levels. The development of toxicity by increasing the administration of VOSO(4) should be avoided. One method was the utilization of vanadyl complexes with coordination compounds that are low-toxic and low-molecular-weight ligands to enhance the permeation of the metal ion to lipid bilayer membrane. Over a decade we have focused on a variety of heterocyclic compounds as bidentate ligands for metal ions. Vanadyl and zinc(II) complexes of 1-substituted 3-hydroxy-2-methyl-4(1H)-pyridinethiones, 4,5,6-substituted 1-hydroxy-2(1H)-pyrimidinones, 4-(p-substituted)phenyl-3-hydroxythiazole-2(3H)-thiones, 3-hydroxypyrone, 1-alkyl- or 1-phenylalkyl-3-hydroxy-2(1H)-pyridinethiones, optically active 1-substituted 3-hydroxy-4(1H)-pyridinethiones, and 5-dialkylsulfonamido- or 5,7-bis(dialkylsulfonamido)-8-hydroxyquinolines were prepared, and their insulin-mimetic activities were evaluated in terms of IC(50) values which stand for a 50% inhibitory concentration of the free fatty acid release from isolated rat adipocytes. In this article, the relationship between the insulin-mimetic activity and the partition coefficient, the chirality, the substituent effect, molecular weight, the pK(a) value, and the coordination mode was discussed. In vivo blood glucose-lowering effects of the vanadyl complex with 1-hydroxy-4,6-dimethyl-2(1H)-pyrimidinone in streptozotocin (STZ)-induced diabetic rats and the zinc(II) complexes with 4-(p-chlorophenyl)thiazole- and 4-methylthiazole-2(3H)-thione in KK-A(y) mice were also discussed.

  6. Metallokinetic analysis of disposition of vanadyl complexes as insulin-mimetics in rats using BCM-ESR method.

    PubMed

    Yasui, H; Takechi, K; Sakurai, H

    2000-02-01

    Among vanadium's wide variety of biological functions, its insulin-mimetic effect is the most interesting and important. Recently, the vanadyl ion (+4 oxidation state of vanadium) and its complexes have been shown to normalize the blood glucose levels of streptozotocin-induced diabetic rats (STZ-rats). During our investigations to find more effective and less toxic vanadyl complexes, the vanadyl-methylpicolinate complex (VO-MPA) was found to exhibit higher insulin-mimetic activity and less toxicity than other complexes, as evaluated by both in vitro and in vivo experiments. Electron spin resonance (ESR) is capable of measuring the paramagnetic species in biological samples. We have developed the in vivo blood circulation monitoring-electron spin resonance (BCM-ESR) method to analyze the ESR signals due to stable organic radicals in real time. In the present investigation, we have applied this method to elucidate the relationship between the blood glucose normalizing effect of VO-MPA and the global disposition of paramagnetic vanadyl species. This paper describes the results of vanadyl species in the circulating blood of rats following intravenous administration of vanadyl compounds. ESR spectra due to the presence of vanadyl species were obtained in the circulating blood, and their pharmacokinetic parameters were estimated using compartment models. The results indicate that vanadyl species are distributed considerably to the peripheral tissues, as estimated by BCM-ESR, and eliminated from the body through the urine, as estimated by ESR at 77 K. The exposure of vanadyl species in the blood was found to be enhanced by VO-MPA treatment. Given these results, we concluded that the pharmacokinetic character of vanadyl species is closely related with the structure and antidiabetic activity of the vanadyl compounds.

  7. Dual stimuli-sensitive dendrimers: Photothermogenic gold nanoparticle-loaded thermo-responsive elastin-mimetic dendrimers.

    PubMed

    Fukushima, Daichi; Sk, Ugir Hossain; Sakamoto, Yasuhiro; Nakase, Ikuhiko; Kojima, Chie

    2015-08-01

    Dendrimers are synthetic macromolecules with unique structures that can work as nanoplatforms for both photothermogenic gold nanoparticles (AuNPs) and thermosensitive elastin-like peptides (ELPs) with valine-proline-glycine-valine-glycine (VPGVG) repeats. In this study, photothermogenic AuNPs were loaded into thermo-responsive elastin-mimetic dendrimers (dendrimers conjugating ELPs at their periphery) to produce dual stimuli-sensitive nanoparticles. Polyamidoamine G4 dendrimers were modified with acetylated VPGVG and (VPGVG)2, and the resulting materials were named ELP1-den and ELP2-den, respectively. The AuNPs were prepared by the reduction of Au ions using a dendrimer-nanotemplated method. The AuNP-loaded elastin-mimetic dendrimers exhibited photothermal properties. ELP1-den and ELP2-den showed similar temperature-dependent changes in their conformations. Phase transitions were observed at around 55°C and 35°C for the AuNP-loaded ELP1-den and AuNP-loaded ELP2-den, respectively, but not for the corresponding PEGylated dendrimer. In contrast to the AuNP-loaded PEGylated dendrimer, AuNP-loaded ELP2-den readily associated with cells and induced efficient photocytotoxicity at 37°C. The cell association and the photocytotoxicity properties of AuNP-loaded ELP2-den could be controlled by temperature. These results therefore suggest that dual stimuli-sensitive dendrimer nanoparticles of this type could be used for photothermal therapy. Copyright © 2015 Elsevier B.V. All rights reserved.

  8. Inhibitor of apoptosis protein expression in glioblastomas and their in vitro and in vivo targeting by SMAC mimetic GDC-0152

    PubMed Central

    Tchoghandjian, A; Soubéran, A; Tabouret, E; Colin, C; Denicolaï, E; Jiguet-Jiglaire, C; El-Battari, A; Villard, C; Baeza-Kallee, N; Figarella-Branger, D

    2016-01-01

    Glioblastomas (GBMs) are the most aggressive primary brain tumors in adult and remain a therapeutic challenge. Targeting key apoptosis regulators with the ultimate aim to restore apoptosis in tumor cells could be an interesting therapeutic strategy. The inhibitors of apoptosis proteins (IAPs) are regulators of cell death and represent attractive targets, especially because they can be antagonized by SMAC mimetics. In this study, we first investigated the expression of cIAP1, cIAP2, XIAP and ML-IAP in human GBM samples and in four different cell lines. We showed that all GBM samples and GBM cell lines expressed all these IAPs, although the expression of each IAP varied from one case to another. We then showed that high level of ML-IAP predicted worse progression-free survival and overall survival in both univariate and multivariate analyses in two independent cohorts of 58 and 43 primary human GBMs. We then used GDC-0152, a SMAC mimetic that antagonizes these IAPs and confirmed that GDC-0152 treatment in vitro decreased IAPs in all the cell lines studied. It affected cell line viability and triggered apoptosis, although the effect was higher in U87MG and GL261 than in GBM6 and GBM9 cell lines. In vivo, GDC-0152 effect on U87MG orthotopic xenografts was dose dependent; it postponed tumor formation and slowed down tumor growth, significantly improving survival of GBM-bearing mice. This study revealed for the first time that ML-IAP protein expression correlates with GBM patient survival and that its antagonist GDC-0152 improves outcome in xenografted mouse. PMID:27490930

  9. ABCA1 (ATP-Binding Cassette Transporter A1) Mediates ApoA-I (Apolipoprotein A-I) and ApoA-I Mimetic Peptide Mobilization of Extracellular Cholesterol Microdomains Deposited by Macrophages.

    PubMed

    Jin, Xueting; Sviridov, Denis; Liu, Ying; Vaisman, Boris; Addadi, Lia; Remaley, Alan T; Kruth, Howard S

    2016-12-01

    We examined the function of ABCA1 (ATP-binding cassette transporter A1) in ApoA-I (apolipoprotein A-I) mobilization of cholesterol microdomains deposited into the extracellular matrix by cholesterol-enriched macrophages. We have also determined whether an ApoA-I mimetic peptide without and with complexing to sphingomyelin can mobilize macrophage-deposited cholesterol microdomains. Extracellular cholesterol microdomains deposited by cholesterol-enriched macrophages were detected with a monoclonal antibody, 58B1. ApoA-I and an ApoA-I mimetic peptide 5A mobilized cholesterol microdomains deposited by ABCA1 +/+ macrophages but not by ABCA1 -/- macrophages. In contrast, ApoA-I mimetic peptide 5A complexed with sphingomyelin could mobilize cholesterol microdomains deposited by ABCA1 -/- macrophages. Our findings show that a unique pool of extracellular cholesterol microdomains deposited by macrophages can be mobilized by both ApoA-I and an ApoA-I mimetic peptide but that mobilization depends on macrophage ABCA1. It is known that ABCA1 complexes ApoA-I and ApoA-I mimetic peptide with phospholipid, a cholesterol-solubilizing agent, explaining the requirement for ABCA1 in extracellular cholesterol microdomain mobilization. Importantly, ApoA-I mimetic peptide already complexed with phospholipid can mobilize macrophage-deposited extracellular cholesterol microdomains even in the absence of ABCA1. © 2016 American Heart Association, Inc.

  10. Loss of prostaglandin F2alpha, but not thromboxane, responsiveness in pregnant human myometrium during labour.

    PubMed

    Fischer, Deborah P; Hutchinson, Jonathon A; Farrar, Diane; O'Donovan, Peter J; Woodward, David F; Marshall, Kay M

    2008-04-01

    Prostaglandins (PG) E2, PGF2alpha and thromboxane (TX) mediate uterine contractility by targeting prostonoid EP, FP and TP receptors respectively. The aim of this study was to elucidate the function of these receptors in isolated human myometrium taken at term gestation prior to and following labour onset. Lower segment myometrial strips were immersed in organ baths in oxygenated Krebs' solution at 37 degrees C and connected to isometric force transducers. After equilibration, spontaneous activity and concentration responses to PGE2, PGF2alpha and U46619 (a stable TX mimetic) were measured as area under the curve and expressed as a percentage of the final contraction induced by hypotonic shock. Results were expressed as arithmetic means+/-s.e.m. and analysed using two-way ANOVA with Bonferroni's post hoc test. Myometrium excised at late gestation displayed the greatest spontaneous activity compared with the tissues taken during labour (P<0.001). Excitation evoked by PGF2alpha (P<0.01) and PGE2 at 10(-5) mol/l were attenuated after labour onset. U46619 consistently stimulated concentration-dependent contractions (P<0.001) and selective antagonists confirmed TP-mediated effects. The maintained responses to TX indicate crucial roles for TP receptors in the muscular tonus of the parturient uterus. This receptor and its secondary messenger system represent effective myometrial targets for tocolytic agents in both pregnancy and labour-associated disorders.

  11. Redistribution of Proximal and Distal Reabsorption of Water and Ions in Rat Kidney After Treatment with Glucagon-Like Peptide-1 Mimetic.

    PubMed

    Natochin, Yu V; Marina, A S; Kutina, A V

    2015-11-01

    Injection of a glucagon-like peptide-1 mimetic accelerated recovery of the initial status of water-salt balance in rats after water or saline load (2.5% NaCl). This effect is mediated by a decrease in proximal fluid reabsorption and change in ion and water transport in the distal part of renal tubules. We developed a new approach to calculation of additional fluid inflow from the proximal tubule to the distal tubule and distal sodium reabsorption under the influence of this mimetic in rats. The expected values corresponded to experimental results, which confirmed our hypothesis on the physiological mechanism for the involvement of the kidneys in the homeostatic effect of glucagon-like peptide-1 under variations in water-salt balance.

  12. A recombinant mimetics of the HIV-1 gp41 prehairpin fusion intermediate fused with human IgG Fc fragment elicits neutralizing antibody response in the vaccinated mice

    SciTech Connect

    Qi, Zhi; Pan, Chungen; Lu, Hong

    2010-07-30

    Research highlights: {yields} One recombinant mimetics of gp41 prehairpin fusion intermediate (PFI) consisting of gp41 N46 sequence, foldon and IgG Fc, designated N46FdFc, was expressed. {yields} N46FdFc-induced antibodies in mice that neutralized HIV-1 infection, inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. {yields} These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines. -- Abstract: HIV-1 gp41 prehairpin fusion intermediate (PFI) composed of three N-terminal heptad repeats (NHR) plays a crucial role in viral fusion and entry and represents an attractive target for anti-HIV therapeutics (e.g., enfuvirtide) andmore » vaccines. In present study, we constructed and expressed two recombinant gp41 PFI mimetics, designated N46Fd and N46FdFc. N46Fd consists of N46 (residues 536-581) in gp41 NHR and foldon (Fd), a trimerization motif. N46FdFc is composed of N46Fd fused with human IgG Fc fragment as an immunoenhancer. We immunized mice with N46 peptide, N46Fd and N46FdFc, respectively, and found that only N46FdFc elicited neutralizing antibody response in mice against infection by HIV-1 strains IIIB (clade B, X4), 92US657 (clade B, R5), and 94UG103 (clade A, X4R5). Anti-N46FdFc antibodies inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines.« less

  13. The SMAC mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor-associated factor 3 degradation in Kupffer cells.

    PubMed

    Liu, Hongxiang; Liao, Rui; He, Kun; Zhu, Xiwen; Li, Peizhi; Gong, Jianping

    2017-05-01

    It was demonstrated that second mitochondria-derived activator of caspases (SMAC) mimetic inhibites tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation and the mitogen-activated protein kinase (MAPK) signaling pathway activation induced by lipopolysaccharide (LPS) in vitro. However, the effect of Smac mimetic in vivo is not clear. The present study was to investigate the role of Smac mimetic in LPS-induced liver injury in mice and its possible mechanism. An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10mg/kg LPS pretreatment with or without Smac mimetic birinapant (30mg/kg body weight). Birinapant significantly improved the survival rate of endotoxemic mice (P<0.05) and attenuated LPS-induced liver pathologic damage and inflammatory response. IL-1 and TNF-α levels in the serum were markedly decreased in birinapant pretreatment mice compared with control mice (P<0.05).The cellular inhibitor of apoptosis protein 1 (cIAP1) expression in liver resident macrophage (Kupffer cells, KCs) was significantly decreased in the Birinapant group compared to the Vehicle group (P<0.05). At the same time, total TRAF3 protein abundance in KCs rapidly declined after LPS stimulation in the Vehicle group. However, it remained constant in the Birinapant group. Moreover, K48-linked polyubiquitination of TRAF3 in KCs was markedly impressed in the birinapant group compared with the control group. At last, the JNK and p38 MAPK activation in KCs was significantly inhibited by birinapant pretreatment (P<0.05). These results suggested that birinapant attenuated liver injury and improved survival rates in endotoxemic mice by inhibited the expression of cIAP1, degradation of TRAF3 and aviation of MAPK signaling pathway. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  14. Distinct Regulatory Mechanisms of the Human Ferritin Gene by Hypoxia and Hypoxia Mimetic Cobalt Chloride at the Transcriptional and Post-transcriptional Levels

    PubMed Central

    Huang, Bo-Wen; Miyazawa, Masaki; Tsuji, Yoshiaki

    2014-01-01

    Cobalt chloride has been used as a hypoxia mimetic because it stabilizes hypoxia inducible factor-1α (HIF1-α) and activates gene transcription through a hypoxia responsive element (HRE). However, differences between hypoxia and hypoxia mimetic cobalt chloride in gene regulation remain elusive. Expression of ferritin, the major iron storage protein, is regulated at the transcriptional and posttranscriptional levels through DNA and RNA regulatory elements. Here we demonstrate that hypoxia and cobalt chloride regulate ferritin heavy chain (ferritin H) expression by two distinct mechanisms. Both hypoxia and cobalt chloride increased HIF1-α but a putative HRE in the human ferritin H gene was not activated. Instead, cobalt chloride but not hypoxia activated ferritin H transcription through an antioxidant responsive element (ARE), to which Nrf2 was recruited. Intriguingly, cobalt chloride downregulated ferritin H protein expression while upregulated other ARE-regulated antioxidant genes in K562 cells. Further characterization demonstrated that cobalt chloride increased interaction between iron regulatory proteins (IRP1 and IRP2) and iron responsive element (IRE) in the 5′UTR of ferritin H mRNA, resulting in translational block of the accumulated ferritin H mRNA. In contrast, hypoxia had marginal effect on ferritin H transcription but increased its translation through decreased IRP1-IRE interaction. These results suggest that hypoxia and hypoxia mimetic cobalt chloride employ distinct regulatory mechanisms through the interplay between DNA and mRNA elements at the transcriptional and post-transcriptional levels. PMID:25172425

  15. Smac mimetic induces an early wave of gene expression via NF-κB and AP-1 and a second wave via TNFR1 signaling.

    PubMed

    Schmidt, Nadine; Haydn, Tinka; Schneider, Ines; Busch, Hauke; Boerries, Melanie; Fulda, Simone

    2018-05-01

    Smac (second mitochondria-derived activator of caspases) mimetics are considered as promising cancer therapeutics, but little is yet known about how they alter gene expression. In this study, we used an unbiased genome-wide expression array to investigate gene regulation induced by the Smac mimetic BV6 in breast cancer cell lines. Here, we discover that tumor necrosis factor (TNF)α/TNF receptor 1 (TNFR1) auto-/paracrine signaling regulates Smac mimetic-stimulated changes in gene expression in a time-dependent manner. TNFR1-independent and -dependent genes account for two subsequent waves of BV6-induced gene expression. While the first wave mostly comprises TNFR1-independent genes and involves nuclear factor-kappa B (NF-κB) and activator protein (AP)-1 transcription factors, the second wave largely depends on TNFR1 signaling. Interestingly, disrupting auto-/paracrine TNFα/TNFR1 signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways, including NF-κB, apoptosis and immune signaling, while activation of mitogen-activated protein kinase (MAPK) signaling occurs also in TNFR1 knockdown cells. Thus, BV6 alters gene expression in a time- as well as TNFR1-dependent manner. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Phylogeny and evolution of Müllerian mimicry in aposematic Dilophotes: evidence for advergence and size-constraints in evolution of mimetic sexual dimorphism.

    PubMed

    Motyka, Michal; Kampova, Lucie; Bocak, Ladislav

    2018-02-27

    Multiple patterns and intraspecific polymorphism should not persist in mutualistic Müllerian systems due to purifying and frequency-dependent selection, but they are commonly identified in nature. We analysed molecular phylogeny and reconstructed dispersal history of 58 species of Dilophotes (Coleoptera: Lycidae) in Asia. Dilophotes colonized the Great Sundas and Malay Peninsula where they joined extensive mimetic communities of net-winged beetles. We identified the brightly bi-coloured males and females which adverged on five occasions to different autochthonous models. This is the first described case of Müllerian sexual dimorphism based on sex-specific body size. We propose that the constraint, i.e. the conservative sexual size dimorphism, forced the unprofitable prey to such complex adaptation in a multi-pattern environment. Although mimetic sexual dimorphism has frequently evolved in Dilophotes, a single pattern has been maintained by both sexes in multiple closely related, sympatrically occurring species. Some patterns may be suboptimal because they are rare, crudely resemble co-mimics, or are newly evolved, but they persist in Müllerian communities for a long time. We assume that failure to closely resemble the most common model can increase the diversity of large Müllerian communities and produce mimetic dimorphism.

  17. EPOR-Based Purification and Analysis of Erythropoietin Mimetic Peptides from Human Urine by Cys-Specific Cleavage and LC/MS/MS

    NASA Astrophysics Data System (ADS)

    Vogel, Matthias; Thomas, Andreas; Schänzer, Wilhelm; Thevis, Mario

    2015-09-01

    The development of a new class of erythropoietin mimetic agents (EMA) for treating anemic conditions has been initiated with the discovery of oligopeptides capable of dimerizing the erythropoietin (EPO) receptor and thus stimulating erythropoiesis. The most promising amino acid sequences have been mounted on various different polymeric structures or carrier molecules to obtain highly active EPO-like drugs exhibiting beneficial and desirable pharmacokinetic profiles. Concomitant with creating new therapeutic options, erythropoietin mimetic peptide (EMP)-based drug candidates represent means to artificially enhance endurance performance and necessitate coverage by sports drug testing methods. Therefore, the aim of the present study was to develop a strategy for the comprehensive detection of EMPs in doping controls, which can be used complementary to existing protocols. Three model EMPs were used to provide proof-of-concept data. Following EPO receptor-facilitated purification of target analytes from human urine, the common presence of the cysteine-flanked core structure of EMPs was exploited to generate diagnostic peptides with the aid of a nonenzymatic cleavage procedure. Sensitive detection was accomplished by targeted-SIM/data-dependent MS2 analysis. Method characterization was conducted for the EMP-based drug peginesatide concerning specificity, linearity, precision, recovery, stability, ion suppression/enhancement, and limit of detection (LOD, 0.25 ng/mL). Additionally, first data for the identification of the erythropoietin mimetic peptides EMP1 and BB68 were generated, demonstrating the multi-analyte testing capability of the presented approach.

  18. Confinement and Stabilization of Fyn SH3 Folding Intermediate Mimetics within the Cavity of the Chaperonin GroEL Demonstrated by Relaxation-Based NMR.

    PubMed

    Libich, David S; Tugarinov, Vitali; Ghirlando, Rodolfo; Clore, G Marius

    2017-02-21

    The interaction of two folding intermediate mimetics of the model protein substrate Fyn SH3 with the chaperonin GroEL, a supramolecular foldase/unfoldase machine, has been investigated by 15 N relaxation-based nuclear magnetic resonance spectroscopy (lifetime line broadening, dark state exchange saturation transfer, and relaxation dispersion). The two mimetics comprise C-terminal truncations of wild-type and triple-mutant (A39V/N53P/V55L) Fyn SH3 in which the C-terminal strand of the SH3 domain is unfolded, while preserving the remaining domain structure. Quantitative analysis of the data reveals that a mobile state of the SH3 domain confined and tethered within the cavity of GroEL, possibly through interactions with the disordered, methionine-rich C-terminal tail(s), can be detected, and that the native state of the folding intermediate mimetics is stabilized by both confinement within and binding to apo GroEL. These data provide a basis for understanding the passive activity of GroEL as a foldase/unfoldase: the unfolded state, in the absence of hydrophobic GroEL-binding consensus sequences, is destabilized within the cavity because of its larger radius of gyration compared to that of the folding intermediate, while the folding intermediate is stabilized relative to the native state because of exposure of a hydrophobic patch that favors GroEL binding.

  19. Interspecific sexual attraction because of convergence in warning colouration: is there a conflict between natural and sexual selection in mimetic species?

    PubMed

    Estrada, C; Jiggins, C D

    2008-05-01

    When species converge in their colour patterns because of mimicry, and those patterns are also used in mate recognition, there is a probability of conflicting selection pressures. Closely related species that mimic one another are particularly likely to face such confusion because of similarities in their courtship behaviour and ecology. We conducted experiments in greenhouse conditions to study interspecific attraction between two mimetic butterfly species, Heliconius erato and Heliconius melpomene. Both species spent considerable time approaching and courting females of the co-mimic species. Experiments using wing models demonstrated the importance of colour pattern in this interspecific attraction. Although males of H. melpomene were attracted to their co-mimics as much as to their own females, H. erato males were more efficient at distinguishing conspecifics, possibly using wing odours. Although preliminary, these results suggest that the use of additional cues may have evolved in H. erato to reduce the cost of convergence in visual signals with H. melpomene. Overall, our results showed that there might be a cost of mimetic convergence because of a reduction in the efficiency of species recognition. Such cost may contribute to explain the apparently stable diversity in Müllerian mimetic patterns in many tropical butterfly assemblages.

  20. Targeted delivery of a model immunomodulator to the lymphatic system: comparison of alkyl ester versus triglyceride mimetic lipid prodrug strategies.

    PubMed

    Han, Sifei; Quach, Tim; Hu, Luojuan; Wahab, Anisa; Charman, William N; Stella, Valentino J; Trevaskis, Natalie L; Simpson, Jamie S; Porter, Christopher J H

    2014-03-10

    A lipophilic prodrug approach has been used to promote the delivery of a model immunomodulator, mycophenolic acid (MPA), to the lymphatic system after oral administration. Lymphatic transport was employed to facilitate enhanced drug uptake into lymphocytes, as recent studies demonstrate that targeted drug delivery to lymph resident lymphocytes may enhance immunomodulatory effects. Two classes of lymph-directing prodrugs were synthesised. Alkyl chain derivatives (octyl mycophenolate, MPA-C8E; octadecyl mycophenolate, MPA-C18E; and octadecyl mycophenolamide, MPA-C18AM), to promote passive partitioning into lipids in lymphatic transport pathways, and a triglyceride mimetic prodrug (1,3-dipalmitoyl-2-mycophenoloyl glycerol, 2-MPA-TG) to facilitate metabolic integration into triglyceride deacylation-reacylation pathways. Lymphatic transport, lymphocyte uptake and plasma pharmacokinetics were assessed in mesenteric lymph and carotid artery cannulated rats following intraduodenal infusion of lipid-based formulations containing MPA or MPA prodrugs. Patterns of prodrug hydrolysis in rat digestive fluid, and cellular re-esterification in vivo, were evaluated to examine the mechanisms responsible for lymphatic transport. Poor enzyme stability and low absorption appeared to limit lymphatic transport of the alkyl derivatives, although two of the three alkyl chain prodrugs - MPA-C18AM (6-fold) and MPA-C18E (13-fold) still increased lymphatic drug transport when compared to MPA. In contrast, 2-MPA-TG markedly increased lymphatic drug transport (80-fold) and drug concentrations in lymphocytes (103-fold), and this was achieved via biochemical incorporation into triglyceride deacylation-reacylation pathways. The prodrug was hydrolysed rapidly to 2-mycophenoloyl glycerol (2-MPA-MG) in the presence of rat digestive fluid, and 2-MPA-MG was subsequently re-esterified in the enterocyte with oleic acid (most likely originating from the co-administered formulation) prior to accessing the

  1. Physiological mechanisms for the increase in renal solute-free water clearance by a glucagon-like peptide-1 mimetic.

    PubMed

    Kutina, Anna V; Marina, Anna S; Shakhmatova, Elena I; Natochin, Yury V

    2013-08-01

    The aim of the present study was to clarify the mechanisms mediating the effect of a glucagon-like peptide-1 (GLP-1) mimetic on solute-free water excretion in rats. The GLP-1 mimetic exenatide (0.05-5.0 nmol/kg, i.m.), alone and in combination with either a vasopressin V2 receptor antagonist (15 nmol/kg, i.p.) or vasopressin (0.01 nmol/kg, i.m.), was injected into control and water-loaded (water 10-50 mL/kg, p.o., or 50 mL/kg of 0.6% NaCl, i.p.) rats to evaluate the role of collecting duct water permeability in the hydrouretic effect. Urinary prostaglandin (PG) E2 excretion and the effects of diclofenac (5 mg/kg, i.m.) and GLP-1 receptor antagonist (0.15 μmol/kg, i.p.) on exenatide action were assessed. The hydrouretic effect of exenatide was equivalent following oral or intraperitoneal water loading, and was proportional to the volume of water administered. Injection of exenatide, under conditions of a maximal decrease in collecting duct water permeability (V2 receptor antagonist administration in water-loaded rats), additionally stimulated solute-free water formation. The GLP-1 receptor antagonist weakened the hydrouretic action of exenatide. Urinary PGE2 excretion increased following water loading (47 ± 6 vs 24 ± 4 ng/kg over a 30 min period) and was enhanced as a result of additional exenatide injection (69 ± 10 ng/kg). Diclofenac and vasopressin delayed the hydrouretic effect of exenatide. The effect of exenatide on solute-free water clearance in water-loaded rats is presumably mediated by stimulation of PGE2 secretion and reinforcement of tubular fluid influx from the proximal tubule to the distal segment of the nephron and collecting duct. © 2013 Wiley Publishing Asia Pty Ltd.

  2. Syntheses of vanadyl and zinc(II) complexes of 1-hydroxy-4,5,6-substituted 2(1H)-pyrimidinones and their insulin-mimetic activities.

    PubMed

    Yamaguchi, Mika; Wakasugi, Kei; Saito, Ryota; Adachi, Yusuke; Yoshikawa, Yutaka; Sakurai, Hiromu; Katoh, Akira

    2006-02-01

    Control of the glucose level in the blood plasma has been achieved in vitro and in vivo by administration of vanadium and zinc in form of inorganic salts. It has been shown that elements are poorly absorbed in their inorganic forms and required high doses which have been associated with undesirable side effects. Many researchers, therefore, have focused on metal complexes that were prepared from VOSO(4) or ZnSO(4) and low-molecular-weight bidentate ligands. Seven kinds of 1-hydroxy-4,6-disubstituted and 1-hydroxy-4,5,6-trisubstituted-2(1H)-pyrimidinones were synthesized by reaction of N-benzyloxyurea and beta-diketones and subsequent removal of the protecting group. Six kinds of 1-hydroxy-4-(substituted)amino-2(1H)-pyrimidinones were synthesized by the substitution reaction of 1-benzyloxy-4-(1',2',4'-triazol-1'-yl)-2(1H)-pyrimidinone with various alkyl amines or amino acids. Treatment with VOSO(4) and ZnSO(4) or Zn(OAc)(2) afforded vanadyl(IV) and zinc(II) complexes which were characterized by means of (1)H NMR, IR, EPR, and UV-vis spectroscopies, and combustion analysis. The in vitro insulin-mimetic activity of these complexes was evaluated from 50% inhibitory concentrations (IC(50)) on free fatty acid (FFA) release from isolated rat adipocytes treated with epinephrine. Vanadyl complexes of 4,6-disubstituted-2(1H)-pyrimidinones showed higher insulin-mimetic activities than those of 4,5,6-trisubstituted ones. On the other hand, Zn(II) complexes showed lower insulin-mimetic activities than VOSO(4) and ZnSO(4) as positive controls. It was found that the balance of the hydrophilicity and/or hydrophobicity is important for higher insulin-mimetic activity. The in vivo insulin-mimetic activity was evaluated with streptozotocin (STZ)-induced diabetic rats. Blood glucose levels were lowered from hyperglycemic to normal levels after the treatment with bis(1,2-dihydro-4,6-dimethyl-2-oxo-1-pyrimidinolato)oxovanadium(IV) by daily intraperitoneal injections. The improvement in

  3. Mussel-mimetic tissue adhesive for fetal membrane repair: a standardized ex vivo evaluation using elastomeric membranes.

    PubMed

    Haller, C M; Buerzle, W; Brubaker, C E; Messersmith, P B; Mazza, E; Ochsenbein-Koelble, N; Zimmermann, R; Ehrbar, M

    2011-07-01

    Iatrogenic preterm premature rupture of membranes (iPPROM), the main complication of invasive interventions in the prenatal period, seriously limits the benefit of diagnostic or surgical prenatal procedures. This study aimed to evaluate preventive plugging of punctured fetal membranes in an ex vivo situation using a new mussel-mimetic tissue adhesive (mussel glue) to inhibit leakage. A novel biomechanical test device that tests the closure of injured membranes under near-physiological conditions was used. Mussel glue, a poly(ethylene glycol)-based hydrogel, was used to seal membrane defects of up to 3 mm in mechanically well-defined elastomeric membranes with three different degrees of stiffness. Elastomeric test membranes were successfully employed for testing mussel glue under well-defined conditions. Mussel glue plugs were distended by up to 94%, which translated to an improved sealing efficiency on elastomeric membranes with high stiffness. For the stiffest membrane tested, a critical burst pressure of 48 mbar (36 mmHg) was accomplished in this ex vivo setting. Mussel glue appears to efficiently seal membrane defects under well-standardized ex vivo conditions. As repaired membranes resist pressures measured in amniotic cavities, mussel glue might represent a novel sealing method for iatrogenic membrane defects. Copyright © 2011 John Wiley & Sons, Ltd.

  4. Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics.

    PubMed

    Dunbar, Richard L; Goel, Harsh; Tuteja, Sony; Song, Wen-Liang; Nathanson, Grace; Babar, Zeeshan; Lalic, Dusanka; Gelfand, Joel M; Rader, Daniel J; Grove, Gary L

    2017-04-01

    Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor , as well as dolor , tumor , and calor , and systemically, heat loss, frigor , chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor / frigor by thermometry. Surprisingly, each stigma's abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

  5. Measuring niacin-associated skin toxicity (NASTy) stigmata along with symptoms to aid development of niacin mimetics[S

    PubMed Central

    Dunbar, Richard L.; Goel, Harsh; Tuteja, Sony; Song, Wen-Liang; Nathanson, Grace; Babar, Zeeshan; Lalic, Dusanka; Gelfand, Joel M.; Rader, Daniel J.; Grove, Gary L.

    2017-01-01

    Though cardioprotective, niacin monotherapy is limited by unpleasant cutaneous symptoms mimicking dermatitis: niacin-associated skin toxicity (NASTy). Niacin is prototypical of several emerging drugs suffering off-target rubefacient properties whereby agonizing the GPR109A receptor on cutaneous immune cells provokes vasodilation, prompting skin plethora and rubor, as well as dolor, tumor, and calor, and systemically, heat loss, frigor, chills, and rigors. Typically, NASTy effects are described by subjective patient-reported perception, at best semi-quantitative and bias-prone. Conversely, objective, quantitative, and unbiased methods measuring NASTy stigmata would facilitate research to abolish them, motivating development of several objective methods. In early drug development, such methods might better predict clinical tolerability in larger clinical trials. Measuring cutaneous stigmata may also aid investigations of vasospastic, ischemic, and inflammatory skin conditions. We present methods to measure NASTy physical stigmata to facilitate research into novel niacin mimetics/analogs, detailing characteristics of each technique following niacin, and how NASTy stigmata relate to symptom perception. We gave niacin orally and measured rubor by colorimetry and white-light spectroscopy, plethora by laser Doppler flowmetry, and calor/frigor by thermometry. Surprisingly, each stigma’s abruptness predicted symptom perception, whereas peak intensity did not. These methods are adaptable to study other rubefacient drugs or dermatologic and vascular disorders. PMID:28119443

  6. RASSF1A and the BH3-only mimetic ABT-737 promote apoptosis in pediatric medulloblastoma cell lines

    PubMed Central

    Levesley, Jane; Lusher, Meryl E.; Lindsey, Janet C.; Clifford, Steven C.; Grundy, Richard; Coyle, Beth

    2011-01-01

    The RASSF1A tumor suppressor is potentially the most important candidate gene identified in medulloblastoma to date, being epigenetically silenced in >79% of primary tumors. However, its functional role has not been previously addressed in this tumor type. Here, we demonstrate that expression of RASSF1A promotes the induction of cell death after activation of both the extrinsic and intrinsic apoptotic pathways in medulloblastoma cells. Treatment of UW228-3 cells stably expressing RASSF1A with an anti-CD95 antibody to induce extrinsic apoptosis and etoposide or cisplatin to activate intrinsic apoptosis augmented tumor cell killing in a caspase-dependent manner. This led to increased activation of the pro-apoptotic BCL-2 family member BAX. On the basis of this knowledge, we demonstrate how the loss of RASSF1A function in medulloblastoma cells might be overcome using the novel BH3-only mimetic ABT-737 in combination with chemotherapeutic agents to target the BCL-2 anti-apoptotic members. We show that ABT-737 increased susceptibility to apoptosis induced by DNA damage regardless of RASSF1A expression status through increased activation of BAX. Our findings identify the RASSF1A tumor suppressor as a promoter of apoptotic signaling pathways. Investigation of its mechanism of action has revealed that these pathways can still be promoted in its absence and how these potentially represent novel therapeutic targets for medulloblastoma. PMID:21880625

  7. Virus-mimetic polyplex particles for systemic and inflammation-specific targeted delivery of large genetic contents.

    PubMed

    Kang, S; Lu, K; Leelawattanachai, J; Hu, X; Park, S; Park, T; Min, I M; Jin, M M

    2013-11-01

    Systemic and target-specific delivery of large genetic contents has been difficult to achieve. Although viruses effortlessly deliver kilobase-long genome into cells, its clinical use has been hindered by serious safety concerns and the mismatch between native tropisms and desired targets. Nonviral vectors, in contrast, are limited by low gene transfer efficiency and inherent cytotoxicity. Here we devised virus-mimetic polyplex particles (VMPs) based on electrostatic self-assembly among polyanionic peptide (PAP), cationic polymer polyethyleneimine (PEI) and nucleic acids. We fused PAP to the engineered ligand-binding domain of integrin αLβ2 to target intercellular adhesion molecule-1 (ICAM-1), an inducible marker of inflammation. Fully assembled VMPs packaged large genetic contents, bound specifically to target molecules, elicited receptor-mediated endocytosis and escaped endosomal pathway, resembling intracellular delivery processes of viruses. Unlike conventional PEI-mediated transfection, molecular interaction-dependent gene delivery of VMPs was unaffected by the presence of serum and achieved higher efficiency without toxicity. By targeting overexpressed ICAM-1, VMPs delivered genes specifically to inflamed endothelial cells and macrophages both in vitro and in vivo. Simplicity and versatility of the platform and inflammation-specific delivery may open up opportunities for multifaceted gene therapy that can be translated into the clinic and treat a broad range of debilitating immune and inflammatory diseases.

  8. Sera from children with autism induce autistic features which can be rescued with a CNTF small peptide mimetic in rats.

    PubMed

    Kazim, Syed Faraz; Cardenas-Aguayo, Maria Del Carmen; Arif, Mohammad; Blanchard, Julie; Fayyaz, Fatima; Grundke-Iqbal, Inge; Iqbal, Khalid

    2015-01-01

    Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism.

  9. Furoxans (1,2,5-Oxadiazole-N-Oxides) as Novel NO Mimetic Neuroprotective and Procognitive Agents

    SciTech Connect

    Schiefer, Isaac T.; VandeVrede, Lawren; Fa

    2012-08-31

    Furoxans (1,2,5-oxadiazole-N-oxides) are thiol-bioactivated NO-mimetics that have not hitherto been studied in the CNS. Incorporation of varied substituents adjacent to the furoxan ring system led to modulation of reactivity toward bioactivation, studied by HPLC-MS/MS analysis of reaction products. Attenuated reactivity unmasked the cytoprotective actions of NO in contrast to the cytotoxic actions of higher NO fluxes reported previously for furoxans. Neuroprotection was observed in primary neuronal cell cultures following oxygen glucose deprivation (OGD). Neuroprotective activity was observed to correlate with thiol-dependent bioactivation to produce NO{sub 2}{sup -}, but not with depletion of free thiol itself. Neuroprotection was abrogated upon cotreatmentmore » with a sGC inhibitor, ODQ, thus supporting activation of the NO/sGC/CREB signaling cascade by furoxans. Long-term potentiation (LTP), essential for learning and memory, has been shown to be potentiated by NO signaling, therefore, a peptidomimetic furoxan was tested in hippocampal slices treated with oligomeric amyloid-{beta} peptide (A{beta}) and was shown to restore synaptic function. The novel observation of furoxan activity of potential therapeutic use in the CNS warrants further studies.« less

  10. Structural ensembles reveal intrinsic disorder for the multi-stimuli responsive bio-mimetic protein Rec1-resilin

    NASA Astrophysics Data System (ADS)

    Balu, Rajkamal; Knott, Robert; Cowieson, Nathan P.; Elvin, Christopher M.; Hill, Anita J.; Choudhury, Namita R.; Dutta, Naba K.

    2015-06-01

    Rec1-resilin is the first recombinant resilin-mimetic protein polymer, synthesized from exon-1 of the Drosophila melanogaster gene CG15920 that has demonstrated unusual multi-stimuli responsiveness in aqueous solution. Crosslinked hydrogels of Rec1-resilin have also displayed remarkable mechanical properties including near-perfect rubber-like elasticity. The structural basis of these extraordinary properties is not clearly understood. Here we combine a computational and experimental investigation to examine structural ensembles of Rec1-resilin in aqueous solution. The structure of Rec1-resilin in aqueous solutions is investigated experimentally using circular dichroism (CD) spectroscopy and small angle X-ray scattering (SAXS). Both bench-top and synchrotron SAXS are employed to extract structural data sets of Rec1-resilin and to confirm their validity. Computational approaches have been applied to these experimental data sets in order to extract quantitative information about structural ensembles including radius of gyration, pair-distance distribution function, and the fractal dimension. The present work confirms that Rec1-resilin is an intrinsically disordered protein (IDP) that displays equilibrium structural qualities between those of a structured globular protein and a denatured protein. The ensemble optimization method (EOM) analysis reveals a single conformational population with partial compactness. This work provides new insight into the structural ensembles of Rec1-resilin in solution.

  11. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia.

    PubMed

    Brumatti, Gabriela; Ma, Chunyan; Lalaoui, Najoua; Nguyen, Nhu-Y; Navarro, Mario; Tanzer, Maria C; Richmond, Jennifer; Ghisi, Margherita; Salmon, Jessica M; Silke, Natasha; Pomilio, Giovanna; Glaser, Stefan P; de Valle, Elisha; Gugasyan, Raffi; Gurthridge, Mark A; Condon, Stephen M; Johnstone, Ricky W; Lock, Richard; Salvesen, Guy; Wei, Andrew; Vaux, David L; Ekert, Paul G; Silke, John

    2016-05-18

    Resistance to chemotherapy is a major problem in cancer treatment, and it is frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a clinical SMAC mimetic, had been designed to mimic the interaction between inhibitor of apoptosis proteins (IAPs) and SMAC/Diablo, thereby relieving IAP-mediated caspase inhibition and promoting apoptosis of cancer cells. We show that acute myeloid leukemia (AML) cells are sensitive to birinapant-induced death and that the clinical caspase inhibitor emricasan/IDN-6556 augments, rather than prevents, killing by birinapant. Deletion of caspase-8 sensitized AML to birinapant, whereas combined loss of caspase-8 and the necroptosis effector MLKL (mixed lineage kinase domain-like) prevented birinapant/IDN-6556-induced death, showing that inhibition of caspase-8 sensitizes AML cells to birinapant-induced necroptosis. However, loss of MLKL alone did not prevent a caspase-dependent birinapant/IDN-6556-induced death, implying that AML will be less likely to acquire resistance to this drug combination. A therapeutic breakthrough in AML has eluded researchers for decades. Demonstrated antileukemic efficacy and safety of the birinapant/emricasan combination in vivo suggest that induction of necroptosis warrants clinical investigation as a therapeutic opportunity in AML. Copyright © 2016, American Association for the Advancement of Science.

  12. Sera from Children with Autism Induce Autistic Features Which Can Be Rescued with a CNTF Small Peptide Mimetic in Rats

    PubMed Central

    Kazim, Syed Faraz; Cardenas-Aguayo, Maria del Carmen; Arif, Mohammad; Blanchard, Julie; Fayyaz, Fatima; Grundke-Iqbal, Inge; Iqbal, Khalid

    2015-01-01

    Autism is a neurodevelopmental disorder characterized clinically by impairments in social interaction and verbal and non-verbal communication skills as well as restricted interests and repetitive behavior. It has been hypothesized that altered brain environment including an imbalance in neurotrophic support during early development contributes to the pathophysiology of autism. Here we report that sera from children with autism which exhibited abnormal levels of various neurotrophic factors induced cell death and oxidative stress in mouse primary cultured cortical neurons. The effects of sera from autistic children were rescued by pre-treatment with a ciliary neurotrophic factor (CNTF) small peptide mimetic, Peptide 6 (P6), which was previously shown to exert its neuroprotective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression. Similar neurotoxic effects and neuroinflammation were observed in young Wistar rats injected intracerebroventricularly with autism sera within hours after birth. The autism sera injected rats demonstrated developmental delay and deficits in social communication, interaction, and novelty. Both the neurobiological changes and the behavioral autistic phenotype were ameliorated by P6 treatment. These findings implicate the involvement of neurotrophic imbalance during early brain development in the pathophysiology of autism and a proof of principle of P6 as a potential therapeutic strategy for autism. PMID:25769033

  13. Mononuclear and binuclear copper(II) complexes of the antiinflammatory drug ibuprofen: synthesis, characterization, and catecholase-mimetic activity.

    PubMed

    Abuhijleh, A L

    1994-09-01

    Two mononuclear copper(II) ibuprofenate adducts with imidazole or 2-methylimidazole and two binuclear copper(II) ibuprofenate adducts with metronidazole or caffeine have been prepared and characterized. Elemental analyses, UV-VIS, IR, EPR, and magnetic moment data for imidazole or 2-methylimidazole adducts are consistent with mononuclear square planar complexes that contain two ibuprofenato ligands and two N-containing imidazole ligands to give essentially a CuO2N2 chromophore. The above data for metronidazole or caffeine adducts are consistent with a binuclear structure as found for copper(II) acetate monohydrate and other copper(II) carboxylate dimers. In these complexes four carboxylate groups are bridging two copper(II) atoms, and two added bases coordinated at axial positions to form CuO4N chromophore around each copper. The catecholase-mimetic catalytic activities of the complexes have been determined by monitoring the formation of o-quinone from catechol. The catalytic activities of the mononuclear complexes are lower than those of the binuclear copper(II) ibuprofenate or its metronidazole or caffeine mono-adducts.

  14. Nanoscopic substructures of raft-mimetic liquid-ordered membrane domains revealed by high-speed single-particle tracking

    NASA Astrophysics Data System (ADS)

    Wu, Hsiao-Mei; Lin, Ying-Hsiu; Yen, Tzu-Chi; Hsieh, Chia-Lung

    2016-02-01

    Lipid rafts are membrane nanodomains that facilitate important cell functions. Despite recent advances in identifying the biological significance of rafts, nature and regulation mechanism of rafts are largely unknown due to the difficulty of resolving dynamic molecular interaction of rafts at the nanoscale. Here, we investigate organization and single-molecule dynamics of rafts by monitoring lateral diffusion of single molecules in raft-containing reconstituted membranes supported on mica substrates. Using high-speed interferometric scattering (iSCAT) optical microscopy and small gold nanoparticles as labels, motion of single lipids is recorded via single-particle tracking (SPT) with nanometer spatial precision and microsecond temporal resolution. Processes of single molecules partitioning into and escaping from the raft-mimetic liquid-ordered (Lo) domains are directly visualized in a continuous manner with unprecedented clarity. Importantly, we observe subdiffusion of saturated lipids in the Lo domain in microsecond timescale, indicating the nanoscopic heterogeneous molecular arrangement of the Lo domain. Further analysis of the diffusion trajectory shows the presence of nano-subdomains of the Lo phase, as small as 10 nm, which transiently trap the lipids. Our results provide the first experimental evidence of non-uniform molecular organization of the Lo phase, giving a new view of how rafts recruit and confine molecules in cell membranes.

  15. Preservation of biological function despite oxidative modification of the apolipoprotein A-I mimetic peptide 4F

    PubMed Central

    White, C. Roger; Datta, Geeta; Buck, Amanda K. W.; Chaddha, Manjula; Reddy, Gautam; Wilson, Landon; Palgunachari, Mayakonda N.; Abbasi, Mohammad; Anantharamaiah, G. M.

    2012-01-01

    Myeloperoxidase (MPO)-derived hypochlorous acid induces changes in HDL function via redox modifications at the level of apolipoprotein A-I (apoA-I). As 4F and apoA-I share structural and functional properties, we tested the hypothesis that 4F acts as a reactive substrate for hypochlorous acid (HOCl). 4F reduced the HOCl-mediated oxidation of the fluorescent substrate APF in a concentration-dependent manner (ED50 ∼ 56 ± 3 μM). This reaction induced changes in the physical properties of 4F. Addition of HOCl to 4F at molar ratios ranging from 1:1 to 3:1 reduced 4F band intensity on SDS-PAGE gels and was accompanied by the formation of a higher molecular weight species. Chromatographic studies showed a reduction in 4F peak area with increasing HOCl and the formation of new products. Mass spectral analyses of collected fractions revealed oxidation of the sole tryptophan (Trp) residue in 4F. 4F was equally susceptible to oxidation in the lipid-free and lipid-bound states. To determine whether Trp oxidation influenced its apoA-I mimetic properties, we monitored effects of HOCl on 4F-mediated lipid binding and ABCA1-dependent cholesterol efflux. Neither property was altered by HOCl. These results suggest that 4F serves as a reactive substrate for HOCl, an antioxidant response that does not influence the lipid binding and cholesterol effluxing capacities of the peptide. PMID:22589558

  16. Selective replication of oncolytic virus M1 results in a bystander killing effect that is potentiated by Smac mimetics.

    PubMed

    Cai, Jing; Lin, Yuan; Zhang, Haipeng; Liang, Jiankai; Tan, Yaqian; Cavenee, Webster K; Yan, Guangmei

    2017-06-27

    Oncolytic virotherapy is a treatment modality that uses native or genetically modified viruses that selectively replicate in and kill tumor cells. Viruses represent a type of pathogen-associated molecular pattern and thereby induce the up-regulation of dozens of cytokines via activating the host innate immune system. Second mitochondria-derived activator of caspases (Smac) mimetic compounds (SMCs), which antagonize the function of inhibitor of apoptosis proteins (IAPs) and induce apoptosis, sensitize tumor cells to multiple cytokines. Therefore, we sought to determine whether SMCs sensitize tumor cells to cytokines induced by the oncolytic M1 virus, thus enhancing a bystander killing effect. Here, we report that SMCs potentiate the oncolytic effect of M1 in vitro, in vivo, and ex vivo. This strengthened oncolytic efficacy resulted from the enhanced bystander killing effect caused by the M1 virus via cytokine induction. Through a microarray analysis and subsequent validation using recombinant cytokines, we identified IL-8, IL-1A, and TRAIL as the key cytokines in the bystander killing effect. Furthermore, SMCs increased the replication of M1, and the accumulation of virus protein induced irreversible endoplasmic reticulum stress- and c-Jun N-terminal kinase-mediated apoptosis. Nevertheless, the combined treatment with M1 and SMCs had little effect on normal and human primary cells. Because SMCs selectively and significantly enhance the bystander killing effect and the replication of oncolytic virus M1 specifically in cancer cells, this combined treatment may represent a promising therapeutic strategy.

  17. Hierarchical Nacre Mimetics with Synergistic Mechanical Properties by Control of Molecular Interactions in Self-Healing Polymers.

    PubMed

    Zhu, Baolei; Jasinski, Nils; Benitez, Alejandro; Noack, Manuel; Park, Daesung; Goldmann, Anja S; Barner-Kowollik, Christopher; Walther, Andreas

    2015-07-20

    Designing the reversible interactions of biopolymers remains a grand challenge for an integral mimicry of mechanically superior biological composites. Yet, they are the key to synergistic combinations of stiffness and toughness by providing sacrificial bonds with hidden length scales. To address this challenge, dynamic polymers were designed with low glass-transition temperature T(g) and bonded by quadruple hydrogen-bonding motifs, and subsequently assembled with high-aspect-ratio synthetic nanoclays to generate nacre-mimetic films. The high dynamics and self-healing of the polymers render transparent films with a near-perfectly aligned structure. Varying the polymer composition allows molecular control over the mechanical properties up to very stiff and very strong films (E≈45 GPa, σ(UTS)≈270 MPa). Stable crack propagation and multiple toughening mechanisms occur in situations of balanced dynamics, enabling synergistic combinations of stiffness and toughness. Excellent gas barrier properties complement the multifunctional property profile. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Structural basis of activation-dependent binding of ligand-mimetic antibody AL-57 to integrin LFA-1

    SciTech Connect

    Zhang, Hongmin; Liu, Jin-huan; Yang, Wei

    2010-09-21

    The activity of integrin LFA-1 ({alpha}{sub L}{beta}{sub 2}) to its ligand ICAM-1 is regulated through the conformational changes of its ligand-binding domain, the I domain of {alpha}{sub L} chain, from an inactive, low-affinity closed form (LA), to an intermediate-affinity form (IA), and then finally, to a high-affinity open form (HA). A ligand-mimetic human monoclonal antibody AL-57 (activated LFA-1 clone 57) was identified by phage display to specifically recognize the affinity-upregulated I domain. Here, we describe the crystal structures of the Fab fragment of AL-57 in complex with IA, as well as in its unligated form. We discuss the structural featuresmore » conferring AL-57's strong selectivity for the high affinity, open conformation of the I domain. The AL-57-binding site overlaps the ICAM-1 binding site on the I domain. Furthermore, an antibody Asp mimics an ICAM Glu by forming a coordination to the metal-ion dependent adhesion site (MIDAS). The structure also reveals better shape complementarity and a more hydrophobic interacting interface in AL-57 binding than in ICAM-1 binding. The results explain AL-57's antagonistic mimicry of LFA-1's natural ligands, the ICAM molecules.« less

  19. Superoxide dismutase/catalase mimetic EUK-134 prevents diaphragm muscle weakness in monocrotalin-induced pulmonary hypertension.

    PubMed

    Himori, Koichi; Abe, Masami; Tatebayashi, Daisuke; Lee, Jaesik; Westerblad, Håkan; Lanner, Johanna T; Yamada, Takashi

    2017-01-01

    Patients with pulmonary hypertension (PH) suffer from inspiratory insufficiency, which has been associated with intrinsic contractile dysfunction in diaphragm muscle. Here, we examined the role of redox stress in PH-induced diaphragm weakness by using the novel antioxidant, EUK-134. Male Wistar rats were randomly divided into control (CNT), CNT + EUK-134 (CNT + EUK), monocrotaline-induced PH (PH), and PH + EUK groups. PH was induced by a single intraperitoneal injection of monocrotaline (60 mg/kg body weight). EUK-134 (3 mg/kg body weight/day), a cell permeable mimetic of superoxide dismutase (SOD) and catalase, was daily intraperitoneally administered starting one day after induction of PH. After four weeks, diaphragm muscles were excised for mechanical and biochemical analyses. There was a decrease in specific tetanic force in diaphragm bundles from the PH group, which was accompanied by increases in: protein expression of NADPH oxidase 2/gp91phox, SOD2, and catalase; 3-nitrotyrosine content and aggregation of actin; glutathione oxidation. Treatment with EUK-134 prevented the force decrease and the actin modifications in PH diaphragm bundles. These data show that redox stress plays a pivotal role in PH-induced diaphragm weakness. Thus, antioxidant treatment can be a promising strategy for PH patients with inspiratory failure.

  20. Mechanism of the G-protein mimetic nanobody binding to a muscarinic G-protein-coupled receptor.

    PubMed

    Miao, Yinglong; McCammon, J Andrew

    2018-03-20

    Protein-protein binding is key in cellular signaling processes. Molecular dynamics (MD) simulations of protein-protein binding, however, are challenging due to limited timescales. In particular, binding of the medically important G-protein-coupled receptors (GPCRs) with intracellular signaling proteins has not been simulated with MD to date. Here, we report a successful simulation of the binding of a G-protein mimetic nanobody to the M 2 muscarinic GPCR using the robust Gaussian accelerated MD (GaMD) method. Through long-timescale GaMD simulations over 4,500 ns, the nanobody was observed to bind the receptor intracellular G-protein-coupling site, with a minimum rmsd of 2.48 Å in the nanobody core domain compared with the X-ray structure. Binding of the nanobody allosterically closed the orthosteric ligand-binding pocket, being consistent with the recent experimental finding. In the absence of nanobody binding, the receptor orthosteric pocket sampled open and fully open conformations. The GaMD simulations revealed two low-energy intermediate states during nanobody binding to the M 2 receptor. The flexible receptor intracellular loops contribute remarkable electrostatic, polar, and hydrophobic residue interactions in recognition and binding of the nanobody. These simulations provided important insights into the mechanism of GPCR-nanobody binding and demonstrated the applicability of GaMD in modeling dynamic protein-protein interactions.

  1. The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic

    PubMed Central

    Bieghs, Liesbeth; Lub, Susanne; Fostier, Karel; Maes, Ken; Van Valckenborgh, Els; Menu, Eline; Johnsen, Hans E.; Overgaard, Michael T.; Larsson, Olle; Axelson, Magnus; Nyegaard, Mette; Schots, Rik; Jernberg-Wiklund, Helena

    2014-01-01

    The ABT-analogous 737, 263 and 199 are BH3 mimetics showing potent anti-myeloma (MM) activity, but only on defined molecular subgroups of MM patients presenting a Bcl-2high/Mcl-1low profile. IGF-1 is a major survival factor in MM regulating the expression of Bcl-2 proteins and might therefore be a resistance factor to these ABT-analogous. We first show that IGF-1 protected human MM cell lines (HMCLs) against ABT-737. Concurrently, the IGF-1 receptor inhibitor picropodophyllin (PPP) synergistically sensitized HMCL, primary human MM and murine 5T33MM cells to ABT-737 and ABT-199 by further decreasing cell viability and enhancing apoptosis. Knockdown of Bcl-2 by shRNA protected MM cells to ABT-737, while Mcl-1 shRNA sensitized the cells. PPP overcame the Bcl-2 dependency of ABT-737, but failed to completely overcome the protective effect of Mcl-1. In vivo, co-treatment of 5T33MM bearing mice significantly decreased tumor burden and prolonged overall survival both in a prophylactic and therapeutic setting. Interestingly, proteasome inhibitor resistant CD138− 5T33MM cells were more sensitive to ABT-737, whereas PPP alone targeted the CD138+ cells more effectively. After co-treatment, both subpopulations were targeted equally. Together, the combination of an IGF-1R inhibitor and an ABT-analogue displays synergistic anti-myeloma activity providing the rational for further (pre)clinical testing. PMID:25008202

  2. Improvement of the antihypertensive capacity of candesartan and trityl candesartan by their SOD mimetic copper(II) complexes.

    PubMed

    Islas, María S; Rojo, Teófilo; Lezama, Luis; Merino, Mercedes Griera; Cortes, María A; Puyol, Manuel Rodriguez; Ferrer, Evelina G; Williams, Patricia A M

    2013-06-01

    Two new complexes [Cu(Cand)(H2O)4] [1] and [Cu2(TCand)4(H2O)2]·4H2O [2] (Cand = candesartan; TCand = trityl candesartan) have been synthesized and thoroughly characterized. The FTIR, Raman, EPR and diffuse reflectance spectra of the solid compounds show a dimeric complex for [2] with carboxylate bridging of the type found in copper(II) acetate. Both elemental analysis and thermal measurements allow the determination of the total stoichiometries of both complexes. The stability measurements show that the compounds are stable in ethanolic solutions at least for 1h, while the preservation of the overall stochiometry for both species in solution has been determined by spectrophotometric titrations. By metal complexation the absence of antioxidant behavior of both sartans has been improved. Complexes [1] and [2] are strong superoxidedismutase mimetic compounds and complex [2] also behaves as a peroxyl radical scavenger. Furthermore, this higher antioxidant activity works in parallel with the improvement of the expansive activity over the angiotensin II-induced contracted human mesangial cells. These new complexes exhibit even higher efficiency as drugs in comparison with the free non-complexed medication with increased antioxidant ability expressing higher capacity to block the angiotensin II contractile effect. This study provides a new insight into the development of copper(II) complexes as potential drugs. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Fabrics produced mimetically during static metamorphism in retrogressed eclogites from the Zermatt-Saas zone, Western Italian Alps

    NASA Astrophysics Data System (ADS)

    McNamara, D. D.; Wheeler, J.; Pearce, M.; Prior, D. J.

    2012-11-01

    Lattice preferred orientations (LPOs) are commonly interpreted to form by dislocation creep. Consequently they are used to infer deformation at the metamorphic grade at which the minerals were stable, especially if those minerals show a shape fabric. Here we show that LPOs can occur through mimicry of a pre-existing LPO, so they formed statically, not during deformation. Omphacite and glaucophane LPOs occur in eclogite facies rocks from the Zermatt-Saas Unit of the Northwest Italian Alps. Barroisite grew during greenschist facies retrogression and has an LPO controlled significantly by the eclogite facies omphacite and glaucophane LPOs, rather than directly by deformation. Using spatially resolved lattice orientation data from the three key minerals, collected using electron backscatter diffraction, we deploy a new technique of interphase misorientation distribution analysis to prove this. Barroisite LPO develops by mimicry of omphacite (via a particular lattice orientation relationship) and by direct topotactic and epitactic replacement of glaucophane. LPO in turn influenced anisotropic grain growth, resulting in a barroisite grain shape fabric. Thus regional retrogression during exhumation of the Zermatt-Saas high-pressure rocks was, in large part, static, rather than dynamic as previously interpreted. In general the possibility of mimetic fabrics forming during metamorphic reactions must be borne in mind when interpreting direct structural observations and seismic anisotropy data in terms of deformation, in both crust and mantle.

  4. CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer.

    PubMed

    Xiang, Jingyu; Hurchla, Michelle A; Fontana, Francesca; Su, Xinming; Amend, Sarah R; Esser, Alison K; Douglas, Garry J; Mudalagiriyappa, Chidananda; Luker, Kathryn E; Pluard, Timothy; Ademuyiwa, Foluso O; Romagnoli, Barbara; Tuffin, Gérald; Chevalier, Eric; Luker, Gary D; Bauer, Michael; Zimmermann, Johann; Aft, Rebecca L; Dembowsky, Klaus; Weilbaecher, Katherine N

    2015-11-01

    The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. ©2015 American Association for Cancer Research.

  5. A synthetic superoxide dismutase/catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin

    PubMed Central

    Doctrow, Susan R.; Lopez, Argelia; Schock, Ashley M.; Duncan, Nathan E.; Jourdan, Megan M.; Olasz, Edit B.; Moulder, John E.; Fish, Brian L.; Mäder, Marylou; Lazar, Jozef; Lazarova, Zelmira

    2012-01-01

    In the event of a radionuclear attack or nuclear accident, the skin would be the first barrier exposed to radiation, though skin injury can progress over days to years following exposure. Chronic oxidative stress has been implicated as being a potential contributor to the progression of delayed radiation-induced injury to skin and other organs. To examine the causative role of oxidative stress in delayed radiation-induced skin injury, including impaired wound healing, we tested a synthetic superoxide dismutase (SOD)/catalase mimetic, EUK-207, in a rat model of combined skin irradiation and wound injury. Administered systemically, beginning 48 h after irradiation, EUK-207 mitigated radiation dermatitis, suppressed indicators of tissue oxidative stress, and enhanced wound healing. Evaluation of gene expression in irradiated skin at 30 days after exposure revealed a significant upregulation of several key genes involved in detoxication of reactive oxygen and nitrogen species. This gene expression pattern was primarily reversed by EUK-207 therapy. These results demonstrate that oxidative stress plays a critical role in the progression of radiation-induced skin injury, and that the injury can be mitigated by appropriate antioxidant compounds administered 48 h after exposure. PMID:23190879

  6. Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages.

    PubMed

    Muse, Evan D; Yu, Shan; Edillor, Chantle R; Tao, Jenhan; Spann, Nathanael J; Troutman, Ty D; Seidman, Jason S; Henke, Adam; Roland, Jason T; Ozeki, Katherine A; Thompson, Bonne M; McDonald, Jeffrey G; Bahadorani, John; Tsimikas, Sotirios; Grossman, Tamar R; Tremblay, Matthew S; Glass, Christopher K

    2018-04-09

    Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia. Copyright © 2018 the Author(s). Published by PNAS.

  7. Bile salt composition is secondary to bile salt concentration in determining hydrocortisone and progesterone solubility in intestinal mimetic fluids.

    PubMed

    Zughaid, Huda; Forbes, Ben; Martin, Gary P; Patel, Nilesh

    2012-01-17

    Simulated intestinal fluids (SIFs) used to assay the solubility of orally administered drugs are typically based on a single bile salt; sodium taurocholate (STC). The aim of this study was to develop mimetic intestinal fluids with a closer similarity to physiological fluids than those reported to date by developing a mixed bile salt (MBS) system (STC, sodium glycodeoxycholate, sodium deoxycholate; 60:39:1) with different concentrations of lecithin, the preponderant intestinal phospholipid. Hydrocortisone and progesterone were used as model drugs to evaluate systematically the influence of SIF composition on solubility. Increasing total bile salt concentration from 0 to 30 mM increased hydrocortisone and progesterone solubility by 2- and ∼25-fold, respectively. Accordingly, higher solubilities were measured in the fed-state compared to the fasted-state SIFs. Progesterone showed the greatest increases in solubility in STC and MBS systems (2-7-fold) compared to hydrocortisone (no significant change; P>0.05) as lecithin concentration was increased. Overall, MBS systems gave similar solubility profiles to STC. In conclusion, the addenda of MBS and lecithin were found to be secondary to the influence of BS concentration. These data provide a foundation for the design of more bio-similar media for pivotal decision-guiding assays in drug development and quality control settings. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Case study of remission in adults with immune thrombocytopenia following cessation of treatment with the thrombopoietin mimetic romiplostim.

    PubMed

    Bussel, James B; Wang, Xuena; Lopez, Angela; Eisen, Melissa

    2016-05-01

    In adults, immune thrombocytopenia (ITP), characterized by platelet counts <100 × 10(9)/l, is typically chronic, with remission reported infrequently ≥3 years post-diagnosis. The thrombopoietin mimetic romiplostim increases platelet counts and reduces use of concomitant ITP medications in chronic ITP. While often perceived as a long-term treatment, dose-adjustment rules allow romiplostim to be discontinued when hemostatic platelet counts are reached, as reported in Amgen trials. Eight romiplostim trials were examined for remission, defined as ≥26 consecutive weeks of platelets ≥50 × 10(9)/l without treatment. Remission was identified in 27 patients; median (quartile 1 [Q1], quartile 3 [Q3]) ITP duration of 2.1 (0.5, 4.2) years, 17/27 (63%) having ITP for >1 year, mean baseline platelets 20.9 × 10(9)/l, median preremission maximum dose 3.0 µg/kg, 12/27 (44%) were splenectomized at baseline, and there were 40-276 cumulative weeks of romiplostim with median time to remission 7.1 months. No clear-cut predictors of remission were apparent; however, a number of patients had ITP for <1 year and received romiplostim for <1 year.

  9. A synthetic superoxide dismutase/catalase mimetic EUK-207 mitigates radiation dermatitis and promotes wound healing in irradiated rat skin.

    PubMed

    Doctrow, Susan R; Lopez, Argelia; Schock, Ashley M; Duncan, Nathan E; Jourdan, Megan M; Olasz, Edit B; Moulder, John E; Fish, Brian L; Mäder, Marylou; Lazar, Jozef; Lazarova, Zelmira

    2013-04-01

    In the event of a radionuclear attack or nuclear accident, the skin would be the first barrier exposed to radiation, though skin injury can progress over days to years following exposure. Chronic oxidative stress has been implicated as being a potential contributor to the progression of delayed radiation-induced injury to skin and other organs. To examine the causative role of oxidative stress in delayed radiation-induced skin injury, including impaired wound healing, we tested a synthetic superoxide dismutase (SOD)/catalase mimetic, EUK-207, in a rat model of combined skin irradiation and wound injury. Administered systemically, beginning 48 hours after irradiation, EUK-207 mitigated radiation dermatitis, suppressed indicators of tissue oxidative stress, and enhanced wound healing. Evaluation of gene expression in irradiated skin at 30 days after exposure revealed a significant upregulation of several key genes involved in detoxication of reactive oxygen and nitrogen species. This gene expression pattern was primarily reversed by EUK-207 therapy. These results demonstrate that oxidative stress has a critical role in the progression of radiation-induced skin injury, and that the injury can be mitigated by appropriate antioxidant compounds administered 48 hours after exposure.

  10. Synergistic cytotoxicity of a prostate cancer-specific immunotoxin in combination with the BH3 mimetic ABT-737.

    PubMed

    Noll, Theresa; Schultze-Seemann, Susanne; Kuckuck, Irina; Michalska, Marta; Wolf, Philipp

    2018-03-01

    In many tumors, including prostate cancer, anti-apoptotic members of the Bcl-2 family are overexpressed and cause cell death resistance, which is a typical hallmark of cancer. Different therapeutic approaches, therefore, aim to restore the death mechanisms for enhanced apoptosis. Our recombinant immunotoxin D7(VL-VH)-PE40 is composed of the scFv D7(VL-VH) against the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer cells and of the cytotoxic domain of the bacterial toxin Pseudomonas Exotoxin A (PE40). Since Pseudomonas Exotoxin A-based immunotoxins are known to preferentially inhibit the expression of the anti-apoptotic protein Mcl-1, the rationale was to test our immunotoxin in combination with the BH3 mimetic ABT-737, which specifically inhibits Bcl-2, Bcl-xl, and Bcl-w for enhanced induction of apoptosis in prostate cancer cells. The immunotoxin showed high and specific binding and cytotoxicity against PSMA expressing prostate cancer cells marked by a direct inhibition of Mcl-1. The combination of the immunotoxin with a subtoxic concentration of ABT-737 caused additive or even synergistic effects, which were based on an enhanced apoptosis induction as detected by poly(ADP-ribose) polymerase (PARP) and Caspase-3 cleavage in Western blot. Our study shows that the combination therapy of immunotoxin plus ABT-737 is a promising approach for the future treatment of advanced prostate cancer to improve therapeutic efficacy and to reduce adverse side effects.

  11. Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic)

    PubMed Central

    Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R.; Matloub, Hani S.; Pritchard, Kirkwood A.; Jaradeh, Safwan S.; Havlik, Robert

    2017-01-01

    Background Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. Methods A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Results Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. Conclusions The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. PMID:26433438

  12. Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic).

    PubMed

    Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R; Matloub, Hani S; Pritchard, Kirkwood A; Jaradeh, Safwan S; Havlik, Robert

    2015-12-01

    Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. Copyright © 2015 National Stroke Association. All rights reserved.

  13. Ionic supramolecular bonds preserve mechanical properties and enable synergetic performance at high humidity in water-borne, self-assembled nacre-mimetics

    NASA Astrophysics Data System (ADS)

    Das, Paramita; Walther, Andreas

    2013-09-01

    Although tremendous effort has been focused on enhancing the mechanical properties of nacre-mimetic materials, conservation of high stiffness and strength against hydration-induced decay of mechanical properties at high humidity remains a fundamental challenge in such water-borne high-performance materials. Herein, we demonstrate that ionic supramolecular bonds, introduced by infiltration of divalent Cu2+ ions, allow efficient stabilization of the mechanical properties of self-assembled water-borne nacre-mimetics based on sustainable sodium carboxymethylcellulose (Na+CMC) and natural sodium montmorillonite nanoclay (Na+MTM) against high humidity (95% RH). The mechanical properties in the highly hydrated state (Young's modulus up to 13.5 GPa and tensile strength up to 125 MPa) are in fact comparable to a range of non-crosslinked nacre-mimetic materials in the dry state. Moreover, the Cu2+-treated nacre-inspired materials display synergetic mechanical properties as found in a simultaneous improvement of stiffness, strength and toughness, as compared to the pristine material. Significant inelastic deformation takes place considering the highly reinforced state. This contrasts the typical behaviour of tight, covalent crosslinks and is suggested to originate from a sacrificial, dynamic breakage and rebinding of transient supramolecular ionic bonds. Considering easy access to a large range of ionic interactions and alteration of counter-ion charge via external stimuli, we foresee responsive and adaptive mechanical properties in highly reinforced and stiff bio-inspired bulk nanocomposites and in other bio-inspired materials, e.g. nanocellulose papers and peptide-based materials.Although tremendous effort has been focused on enhancing the mechanical properties of nacre-mimetic materials, conservation of high stiffness and strength against hydration-induced decay of mechanical properties at high humidity remains a fundamental challenge in such water-borne high

  14. Protective effects of a superoxide dismutase mimetic and peroxynitrite decomposition catalysts in endotoxin-induced intestinal damage.

    PubMed

    Salvemini, D; Riley, D P; Lennon, P J; Wang, Z Q; Currie, M G; Macarthur, H; Misko, T P

    1999-06-01

    1. The relative contributions of superoxide anion (O2-) and peroxynitrite (PN) were evaluated in the pathogenesis of intestinal microvascular damage caused by the intravenous injection of E. coli lipopolysaccharide (LPS) in rats. The superoxide dismutase mimetic (SODm) SC-55858 and the active peroxynitrite decomposition catalysts 5,10,15,20-tetrakis(2,4,6-trimethyl-3,5-disulphonatophenyl)-por phyrinato iron (III) and 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)-porphyrinato iron (III) (FeTMPS, FeTMPyP respectively) were used to assess the roles of O2- and PN respectively. 2. The intravenous injection of LPS elicited an inflammatory response that was characterized by a time-dependent infiltration of neutrophils, lipid peroxidation, microvascular leakage (indicative of microvascular damage), and epithelial cell injury in both the duodenum and jejunum. 3. Administration of the SODm SC-55858, FeTMPS or FeTMPyP at 3 h post LPS reduced the subsequent increase in microvascular leakage, lipid peroxidation and epithelial cell injury. Inactive peroxynitrite decomposition catalysts exhibited no protective effects. Only, SC-55858 inhibited neutrophil infiltration. 4. Our results suggest that O2 and peroxynitrite play a significant role in the pathogenesis of duodenal and intestinal injury during endotoxaemia and that their remoyal by SODm and peroxynitrite decomposition catalysts offers a novel approach to the treatment of septic shock or clinical conditions of gastrointestinal inflammation. Furthermore, the remarkable protection of the intestinal epithelium by these agents suggests their use during chemo- and radiation therapy, cancer treatments characterized by gastrointestinal damage. Potential mechanisms through which these radicals evoke damage are discussed.

  15. Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration.

    PubMed

    Singh, Sandeep; Singh, Abhishek Kumar; Garg, Geetika; Rizvi, Syed Ibrahim

    2018-01-15

    In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Fisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. MLN2238 synergizes BH3 mimetic ABT-263 in castration-resistant prostate cancer cells by induction of NOXA.

    PubMed

    Wei, Xinghua; Zhou, Ping; Lin, Xuanting; Lin, Yurong; Wu, Sifeng; Diao, Pengfei; Xie, Haiqing; Xie, Keji; Tang, Ping

    2014-10-01

    Patients undergoing androgen blockade therapy develop castration-resistant prostate cancer (CRPC), which is associated with Bcl-2 upregulation and results in disease progression and death. In recent years, promising therapeutic agents, such as the BH3-only mimetic ABT-263 and proteasome inhibitors, have been developed and widely evaluated against a broad spectrum of cancer types, including prostate cancer, alone or in combination with other chemotherapeutic agents. In this study, the antitumor efficacy of ABT-263 and MLN2238 were evaluated as single agents and in combination in four CRPC cell lines: PC3, C4-2B, C4-2, and DU145. The viability of the treated cells and markers of apoptosis were assayed. Protein-protein interactions were analyzed by co-immunoprecipitation in drug-treated cells. Lentivirus-mediated short hairpin RNA was used to knockdown Bax, Mcl-1, and NOXA expressions. We found that ABT-263 and MLN2238 alone exhibited a mild cytotoxicity, and in combination, they elicited a synergistic cytotoxic effect in CRPC cells. The cell apoptosis induced by the combination drug treatment was evidenced by enhanced caspase-3 and Poly (ADP-ribose) polymerase (PARP) cleavage, and annexin-V-positive staining was significantly depleted by Bax knockdown. MLN2238 treatment upregulated NOXA and Mcl-1 expression, leading NOXA/Mcl-1 complexes to disassociate Bak from its complexes with Mcl-1 and enhancing ABT263-triggered Bax activation. NOXA knockdown by short hairpin RNA significantly attenuated the cytotoxicity of ABT-263 and MLN2238 co-administration. In conclusion, MLN2238 and ABT-263 synergistically triggered apoptosis in CRPC cells by upregulating NOXA and activating Bax, indicating a promising therapeutic strategy for the treatment of CRPC.

  17. Chemical ultraviolet absorbers topically applied in a skin barrier mimetic formulation remain in the outer stratum corneum of porcine skin.

    PubMed

    Haque, T; Crowther, J M; Lane, M E; Moore, D J

    2016-08-20

    The objective of the present study was to evaluate the fate of three chemical sunscreens, isoamyl p-methoxycinnamate (IPMC), diethylamino hydroxybenzoyl hexyl benzoate (DHHB), and bis-ethylhexylphenol methoxyphenyl triazine (BEMT), topically applied to mammalian skin from a skin barrier mimetic oil-in-water formulation. High Performance Liquid Chromatography (HPLC) methods were developed for the analysis of each molecule and validated. Franz cell permeation studies were conducted following application of finite doses of the formulations to excised porcine skin. A vehicle formulation containing no sunscreens was evaluated as a control. Permeation studies were conducted for 12h after which full mass balance studies were carried out. Analysis of individual UV sunscreens was achieved with HPLC following application of the formulation to the skin with no interference from the vehicle components. No skin permeation of any of the chemical sunscreens was evident after 12h. While sunscreens were detected in up to 12 tape strips taken from the SC, 87% or more of the applied doses recovered in the first 5 tape strips. When corrected for the amount of protein removed per tape strip this corresponded to a penetration depth in porcine stratum corneum of ∼1.7μm. Mass balance studies indicated total recovery values were within accepted guidelines for cosmetic formulations. Overall, only superficial penetration into the SC was observed for each compound. These findings are consistent with the physicochemical properties of the selected UV absorbing molecules and their formulation into an ordered biomimetic barrier formulation thus support their intended use in topical consumer formulations designed to protect from UV exposure. To our knowledge this is the first report of depth profiling of chemical sunscreens in the SC that combines tape stripping and protein determination following in vitro Franz cell studies. Copyright © 2016 Elsevier B.V. All rights reserved.

  18. Superoxide dismutase mimetic, tempol, aggravates renal injury in advanced-stage stroke-prone spontaneously hypertensive rats.

    PubMed

    Sugama, Ikuko; Kohagura, Kentaro; Yamazato, Masanobu; Nakamura, Takuto; Shinzato, Tomoko; Ohya, Yusuke

    2014-03-01

    The aim of this study was to determine whether antioxidant therapy could relieve hypertension and retard the progression of renal damage in advanced-stage hypertensive rats. Twenty-four-week-old spontaneously hypertensive stroke-prone rats were treated for 8 weeks with the superoxide dismutase mimetic tempol, low-dose or high-dose candesartan (an angiotensin receptor blocker), or hydralazine, and blood pressure and renal damage were compared. Elevated blood pressure and renal damage with heterogeneity were present after 8 weeks, with greater glomerulosclerosis in the juxtamedullary glomeruli than in the superficial glomeruli. Although both tempol and candesartan effectively reduced reactive oxygen species production in the kidney, tempol did not decrease blood pressure and exacerbated urine protein and histological damage, such as glomerulosclerosis and interstitial fibrosis, particularly in juxtamedullary nephrons (tempol vs. untreated: glomerulosclerosis index, 2.0 vs. 1.5, P<0.01; fibrosis, 15 vs. 10%, P<0.001). In contrast, high-dose candesartan and hydralazine prevented these forms of renal damage with lowering blood pressure. Low-dose candesartan also prevented this renal damage without lowering blood pressure. Moreover, there were increased numbers of larger and smaller glomeruli in the juxtamedullary cortex of tempol-treated rats, suggesting that changes in glomerular hemodynamics may be responsible for the exacerbation of glomerulosclerosis. Both candesartan- and hydralazine-treated rats had glomeruli that were slightly decreased in size. These results suggest that single-antioxidant therapy starting at an advanced-stage may be ineffective for hypertension and rather exacerbate renal damage in nonsalt loaded SHRSP. Furthermore, lowering blood pressure and inhibiting the renin-angiotensin system could be critical for slowing the progression of hypertensive renal damage at an advanced stage.

  19. Tempol, a superoxide dismutase mimetic agent, ameliorates cisplatin-induced nephrotoxicity through alleviation of mitochondrial dysfunction in mice.

    PubMed

    Ahmed, Lamiaa A; Shehata, Nagwa I; Abdelkader, Noha F; Khattab, Mahmoud M

    2014-01-01

    Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice. Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma. This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.

  20. In vitro permeation and disposition of niacinamide in silicone and porcine skin of skin barrier-mimetic formulations.

    PubMed

    Haque, Tasnuva; Lane, Majella E; Sil, Bruno C; Crowther, Jonathan M; Moore, David J

    2017-03-30

    Niacinamide (NIA) is an amide form of vitamin B3 which is used in cosmetic formulations to improve various skin conditions and it has also been shown to increase stratum corneum thickness following repeated application. In this study, three doses (5, 20 and 50μL per cm 2 ) of two NIA containing oil-in-water skin barrier-mimetic formulations were evaluated in silicone membrane and porcine ear skin and compared with a commercial control formulation. Permeation studies were conducted over 24h in Franz cells and at the end of the experiment membranes were washed and niacinamide was extracted. For the three doses, retention or deposition of NIA was generally higher in porcine skin compared with silicone membrane, consistent with the hydrophilic nature of the active. Despite the control containing a higher amount of active, comparable amounts of NIA were deposited in skin for all formulations for all doses; total skin absorption values (permeation and retention) of NIA were also comparable across all formulations. For infinite (50μL) and finite (5μL) doses the absolute permeation of NIA from the control formulation was significantly higher in porcine skin compared with both test formulations. This likely reflects differences in formulation components and/or presence of skin penetration enhancers in the formulations. Higher permeation for the 50 and 20μL dose was also evident in porcine skin compared with silicone membrane but the opposite is the case for the finite dose. The findings point to the critical importance of dose and occlusion when evaluating topical formulations in vitro and also the likelihood of exaggerated effects of excipients on permeation at infinite and pseudo-finite dose applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Synthesis and Characterization of Elastin-Mimetic Hybrid Polymers with Multiblock, Alternating Molecular Architecture and Elastomeric Properties

    PubMed Central

    Grieshaber, Sarah E.; Farran, Alexandra J. E.; Lin-Gibson, Sheng; Kiick, Kristi L.; Jia, Xinqiao

    2009-01-01

    We are interested in developing elastin–mimetic hybrid polymers (EMHPs) that capture the multiblock molecular architecture of tropoelastin as well as the remarkable elasticity of mature elastin. In this study, multiblock EMHPs containing flexible synthetic segments based on poly(ethylene glycol) (PEG) alternating with alanine-rich, lysine-containing peptides were synthesized by step-growth polymerization using α,ω-azido-PEG and alkyne-terminated AKA3KA (K = lysine, A = alanine) peptide, employing orthogonal click chemistry. The resulting EMHPs contain an estimated three to five repeats of PEG and AKA3KA and have an average molecular weight of 34 kDa. While the peptide alone exhibited α-helical structures at high pH, the fractional helicity for EMHPs was reduced. Covalent cross-linking of EMHPs with hexamethylene diisocyanate (HMDI) through the lysine residue in the peptide domain afforded an elastomeric hydrogel (xEMHP) with a compressive modulus of 0.12 MPa when hydrated. The mechanical properties of xEMHP are comparable to a commercial polyurethane elastomer (Tecoflex SG80A) under the same conditions. In vitro toxicity studies showed that while the soluble EMHPs inhibited the growth of primary porcine vocal fold fibroblasts (PVFFs) at concentrations ≥0.2 mg/mL, the cross-linked hybrid elastomers did not leach out any toxic reagents and allowed PVFFs to grow and proliferate normally. The hybrid and modular approach provides a new strategy for developing elastomeric scaffolds for tissue engineering. PMID:19763157

  2. Aminoacid-derivatised picolinato-oxidovanadium(IV) complexes: characterisation, speciation and ex vivo insulin-mimetic potential.

    PubMed

    Esbak, Hossein; Enyedy, Eva A; Kiss, Tamás; Yoshikawa, Yutaka; Sakurai, Hiromu; Garribba, Eugenio; Rehder, Dieter

    2009-04-01

    The proligands PicMe-AaR (PicMe=methoxipicolyl-5-amide, where the amide substituent is an amino acid AaR=HisH, HisMe, IleH, IleMe, TrpH, TrpMe, HTyrEt, tBuTyrMe, HThrMe, tBuThrMe) and the complexes [VO(Pic-AaR)(2)] have been synthesised and characterised. A detailed EPR study of the VO(2+)/Pic-His systems in water revealed the predominance of the complex [VO(Pic-His)H(2)O] in the pH range 2-6, with tridentate coordination of Pic-His via the picolinate moiety and imidazole-Ndelta. Speciation analyses of the binary systems VO(2+)/Pic-Aa (Aa=His, Ile, Trp) and the ternary systems VO(2+)/Pic-Aa/B (Aa=His, Ile; B=citrate (cit), lactate (lac), phosphate) showed a predominance of the ternary complexes [VO(Pic-Aa)(cit/lac)] and [VO(Pic-Aa)(cit/lac)OH](-) in the physiological pH regime. If, in addition, human serum albumin (HAS) and apotransferrin (Tf) are present, with all of the low and high molecular mass constituents in their blood serum concentrations, about two thirds of VO(2+) is bound to the protein, while there is still a sizable amount of ternary complex [VO(Pic-Aa)(cit/lac)] present (about 1/4 for Pic-His and 1/3 for Pic-Ile) when the vanadium(IV) concentration is relatively high; at lower concentrations Tf is the predominant binder. Insulin-mimetic studies for VO(2+)/Pic-Aa (Aa=His, Ile, Tyr and Trp), based on a lipolysis assay with rat adipocytes, provided IC(50) values of 0.41(1) for VO(2+)/Pic-His and VO(2+)/Pic-Ile, which compares with 0.87(17) for VOSO(4).

  3. High-resolution NMR characterization of a spider-silk mimetic composed of 15 tandem repeats and a CRGD motif

    PubMed Central

    McLachlan, Glendon D; Slocik, Joseph; Mantz, Robert; Kaplan, David; Cahill, Sean; Girvin, Mark; Greenbaum, Steve

    2009-01-01

    Multidimensional solution NMR spectroscopic techniques have been used to obtain atomic level information about a recombinant spider silk construct in hexafluoro-isopropanol (HFIP). The synthetic 49 kDa silk-like protein mimics authentic silk from Nephila clavipes, with the inclusion of an extracellular matrix recognition motif. 2D 1H-15N HSQC NMR spectroscopy reveals 33 cross peaks, which were assigned to amino acid residues in the semicrystalline repeat units. Signals from the amorphous segments in the primary sequence were weak and broad, suggesting that this region is highly dynamic and undergoing conformational exchange. An analysis of the deviations of the 13Cα, 13Cβ, and 13CO chemical shifts relative to the expected random coil values reveals two highly α-helical regions from amino acid 12–19 and 26–32, which comprise the polyalanine track and a GGLGSQ sequence. This finding is further supported by φ-value analysis and sequential and medium-range NOE interactions. Pulsed field gradient NMR measurements indicate that the topology of the silk mimetic in HFIP is nonglobular. Moreover, the 3D 15N-NOESY HSQC spectrum exhibits few long-range NOEs. Similar spectral features have been observed for repeat modules in other polypeptides and are characteristic of an elongated conformation. The results provide a residue-specific description of a silk sequence in nonaqueous solution and may be insightful for understanding the fold and topology of highly concentrated, stable silk before spinning. Additionally, the insights obtained may find application in future design and large-scale production and storage of synthetic silks in organic solvents. PMID:19177364

  4. High-resolution NMR characterization of a spider-silk mimetic composed of 15 tandem repeats and a CRGD motif.

    PubMed

    McLachlan, Glendon D; Slocik, Joseph; Mantz, Robert; Kaplan, David; Cahill, Sean; Girvin, Mark; Greenbaum, Steve

    2009-01-01

    Multidimensional solution NMR spectroscopic techniques have been used to obtain atomic level information about a recombinant spider silk construct in hexafluoro-isopropanol (HFIP). The synthetic 49 kDa silk-like protein mimics authentic silk from Nephila clavipes, with the inclusion of an extracellular matrix recognition motif. 2D (1)H-(15)N HSQC NMR spectroscopy reveals 33 cross peaks, which were assigned to amino acid residues in the semicrystalline repeat units. Signals from the amorphous segments in the primary sequence were weak and broad, suggesting that this region is highly dynamic and undergoing conformational exchange. An analysis of the deviations of the (13)C(alpha), (13)C(beta), and (13)CO chemical shifts relative to the expected random coil values reveals two highly alpha-helical regions from amino acid 12-19 and 26-32, which comprise the polyalanine track and a GGLGSQ sequence. This finding is further supported by phi-value analysis and sequential and medium-range NOE interactions. Pulsed field gradient NMR measurements indicate that the topology of the silk mimetic in HFIP is nonglobular. Moreover, the 3D (15)N-NOESY HSQC spectrum exhibits few long-range NOEs. Similar spectral features have been observed for repeat modules in other polypeptides and are characteristic of an elongated conformation. The results provide a residue-specific description of a silk sequence in nonaqueous solution and may be insightful for understanding the fold and topology of highly concentrated, stable silk before spinning. Additionally, the insights obtained may find application in future design and large-scale production and storage of synthetic silks in organic solvents.

  5. Activation of silenced tumor suppressor genes in prostate cancer cells by a novel energy restriction-mimetic agent.

    PubMed

    Lin, Hsiang-Yu; Kuo, Yi-Chiu; Weng, Yu-I; Lai, I-Lu; Huang, Tim H-M; Lin, Shuan-Pei; Niu, Dau-Ming; Chen, Ching-Shih

    2012-12-01

    Targeting tumor metabolism by energy restriction-mimetic agents (ERMAs) has emerged as a strategy for cancer therapy/prevention. Evidence suggests a mechanistic link between ERMA-mediated antitumor effects and epigenetic gene regulation. Microarray analysis showed that a novel thiazolidinedione-derived ERMA, CG-12, and glucose deprivation could suppress DNA methyltransferase (DNMT)1 expression and reactivate DNA methylation-silenced tumor suppressor genes in LNCaP prostate cancer cells. Thus, we investigated the effects of a potent CG-12 derivative, CG-5, vis-à-vis 2-deoxyglucose, glucose deprivation and/or 5-aza-deoxycytidine, on DNMT isoform expression (Western blotting, RT-PCR), DNMT1 transcriptional activation (luciferase reporter assay), and expression of genes frequently hypermethylated in prostate cancer (quantitative real-time PCR). Promoter methylation was assessed by pyrosequencing analysis. SiRNA-mediated knockdown and ectopic expression of DNMT1 were used to validate DNMT1 as a target of CG-5. CG-5 and glucose deprivation upregulated the expression of DNA methylation-silenced tumor suppressor genes, including GADD45a, GADD45b, IGFBP3, LAMB3, BASP1, GPX3, and GSTP1, but also downregulated methylated tumor/invasion-promoting genes, including CD44, S100A4, and TACSTD2. In contrast, 5-aza-deoxycytidine induced global reactivation of these genes. CG-5 mediated these epigenetic effects by transcriptional repression of DNMT1, which was associated with reduced expression of Sp1 and E2F1. SiRNA-mediated knockdown and ectopic expression of DNMT1 corroborated DNMT1's role in the modulation of gene expression by CG-5. Pyrosequencing revealed differential effects of CG-5 versus 5-aza-deoxycytidine on promoter methylation in these genes. These findings reveal a previously uncharacterized epigenetic effect of ERMAs on DNA methylation-silenced tumor suppressor genes, which may foster novel strategies for prostate cancer therapy. Copyright © 2012 Wiley Periodicals

  6. Ochre Bathing of the Bearded Vulture: A Bio-Mimetic Model for Early Humans towards Smell Prevention and Health

    PubMed Central

    Tributsch, Helmut

    2016-01-01

    Simple Summary The once widespread bearded vulture (Gypaetus barbatus) has the habit of bathing its polluted feathers and skin in red iron oxide-ochre-tainted water puddles. Primitive man may have tried to find out why: ochre is active in sunlight producing aggressive chemical species. They can kill viruses and bacteria and convert smelly organic substances into volatile neutral carbon dioxide gas. There is consequently a sanitary reason for the vulture’s habit of bathing in red ochre mud and this explains why prehistoric people included ochre use into their habits and rituals. Abstract Since primordial times, vultures have been competing with man for animal carcasses. One of these vultures, the once widespread bearded vulture (Gypaetus barbatus), has the habit of bathing its polluted feathers and skin in red iron oxide - ochre - tainted water puddles. Why? Primitive man may have tried to find out and may have discovered its advantages. Red ochre, which has accompanied human rituals and everyday life for more than 100,000 years, is not just a simple red paint for decoration or a symbol for blood. As modern experiments demonstrate, it is active in sunlight producing aggressive chemical species. They can kill viruses and bacteria and convert smelly organic substances into volatile neutral carbon dioxide gas. In this way, ochre can in sunlight sterilize and clean the skin to provide health and comfort and make it scentless, a definitive advantage for nomadic meat hunters. This research thus also demonstrates a sanitary reason for the vulture’s habit of bathing in red ochre mud. Prehistoric people have therefore included ochre use into their rituals, especially into those in relation to birth and death. Significant ritual impulses during evolution of man may thus have developed bio-mimetically, inspired from the habits of a vulture. It is discussed how this health strategy could be developed to a modern standard helping to fight antibiotics-resistant bacteria in

  7. Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice

    PubMed Central

    Ahmed, Lamiaa A.; Shehata, Nagwa I.; Abdelkader, Noha F.; Khattab, Mahmoud M.

    2014-01-01

    Background Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice. Methods and Findings Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I–IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma. Conclusion This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction

  8. Differential effect triggered by a heparan mimetic of the RGTA family preventing oral mucositis without tumor protection.

    PubMed

    Mangoni, Monica; Yue, Xiaoli; Morin, Christophe; Violot, Dominique; Frascogna, Valerie; Tao, Yungan; Opolon, Paule; Castaing, Marine; Auperin, Anne; Biti, Giampaolo; Barritault, Denis; Vozenin-Brotons, Marie-Catherine; Deutsch, Eric; Bourhis, Jean

    2009-07-15

    Oral mucositis is a common side effect induced by radio/chemotherapy in patients with head and neck cancer. Although it dramatically impairs patient quality of life, no efficient and safe therapeutic solution is available today. Therefore, we investigated the protective efficacy of a new heparan mimetic biopolymer, RGTA-OTR4131, used alone or in combination with amifostine, for oral mucositis and simultaneously evaluated its effect on tumor growth in vitro and in vivo. A single dose of 16.5 Gy was selectively delivered to the snout of mice, and the effects of OTR4131 or amifostine-OTR4131 were analyzed by macroscopic scoring and histology. The effect of OTR4131 administration on tumor growth was then investigated in vitro and in xenograft models using two cell lines (HEP-2 and HT-29). Amifostine and OTR4131 significantly decreased the severity and duration of lip mucosal reactions. However, amifostine has to be administered before irradiation, whereas the most impressive protection was obtained when OTR4131 was injected 24 h after irradiation. In addition, OTR4131 was well tolerated, and the combination of amifostine and OTR4131 further enhanced mucosal protection. At the tumor level, OTR4131 did not modify HEP-2 cell line clonogenic survival in vitro or protect xenografted tumor cells from radiotherapy. Of interest, high doses of OTR4131 significantly decreased clonogenic survival of HT-29 cells. RGTAs-OTR4131 is a well-tolerated, natural agent that effectively reduces radio-induced mucositis without affecting tumor sensitivity to irradiation. This suggests a possible transfer into the clinic for patients' benefit.

  9. The superoxide dismutase mimetic tempol does not alleviate glucocorticoid-mediated rarefaction of rat skeletal muscle capillaries.

    PubMed

    Mandel, Erin R; Dunford, Emily C; Abdifarkosh, Ghoncheh; Turnbull, Patrick C; Perry, Christopher G R; Riddell, Michael C; Haas, Tara L

    2017-05-01

    Sustained elevations in circulating glucocorticoids elicit reductions in skeletal muscle microvascular content, but little is known of the underlying mechanisms. We hypothesized that glucocorticoid-induced oxidative stress contributes to this phenomenon. In rats that were implanted with corticosterone (CORT) or control pellets, CORT caused a significant decrease in muscle glutathione levels and a corresponding increase in protein carbonylation, an irreversible oxidative modification of proteins. Decreased endothelial nitric oxide synthase and increased endothelin-1 mRNA levels were detected after 9 days of CORT, and blood flow to glycolytic muscles was diminished. Control and CORT rats were treated concurrently with drinking water containing the superoxide dismutase mimetic tempol (172 mg/L) or the α -1 adrenergic receptor antagonist prazosin (50 mg/L) for 6 or 16 days. Both tempol and prazosin alleviated skeletal muscle protein carbonylation. Tempol failed to prevent CORT-mediated capillary rarefaction and was ineffective in restoring skeletal muscle blood flow. In contrast, prazosin blocked capillary rarefaction and restored skeletal muscle blood flow to control levels. The failure of tempol to prevent CORT-induced skeletal muscle microvascular rarefaction does not support a dominant role of superoxide-induced oxidative stress in this process. Although a decrease in protein carbonylation was observed with prazosin treatment, our data suggest that the maintenance of skeletal muscle microvascular content is related more closely with counteracting the CORT-mediated influence on skeletal muscle vascular tone. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  10. Peptide Mimetic of the S100A4 Protein Modulates Peripheral Nerve Regeneration and Attenuates the Progression of Neuropathy in Myelin Protein P0 Null Mice

    PubMed Central

    Moldovan, Mihai; Pinchenko, Volodymyr; Dmytriyeva, Oksana; Pankratova, Stanislava; Fugleholm, Kåre; Klingelhofer, Jorg; Bock, Elisabeth; Berezin, Vladimir; Krarup, Christian; Kiryushko, Darya

    2013-01-01

    We recently found that S100A4, a member of the multifunctional S100 protein family, protects neurons in the injured brain and identified two sequence motifs in S100A4 mediating its neurotrophic effect. Synthetic peptides encompassing these motifs stimulated neuritogenesis and survival in vitro and mimicked the S100A4-induced neuroprotection in brain trauma. Here, we investigated a possible function of S100A4 and its mimetics in the pathologies of the peripheral nervous system (PNS). We found that S100A4 was expressed in the injured PNS and that its peptide mimetic (H3) affected the regeneration and survival of myelinated axons. H3 accelerated electrophysiological, behavioral and morphological recovery after sciatic nerve crush while transiently delaying regeneration after sciatic nerve transection and repair. On the basis of the finding that both S100A4 and H3 increased neurite branching in vitro, these effects were attributed to the modulatory effect of H3 on initial axonal sprouting. In contrast to the modest effect of H3 on the time course of regeneration, H3 had a long-term neuroprotective effect in the myelin protein P0 null mice, a model of dysmyelinating neuropathy (Charcot-Marie-Tooth type 1 disease), where the peptide attenuated the deterioration of nerve conduction, demyelination and axonal loss. From these results, S100A4 mimetics emerge as a possible means to enhance axonal sprouting and survival, especially in the context of demyelinating neuropathies with secondary axonal loss, such as Charcot-Marie-Tooth type 1 disease. Moreover, our data suggest that S100A4 is a neuroprotectant in PNS and that other S100 proteins, sharing high homology in the H3 motif, may have important functions in PNS pathologies. PMID:23508572

  11. The radiosensitizing activity of the SMAC-mimetic, Debio 1143, is TNFα-mediated in head and neck squamous cell carcinoma.

    PubMed

    Matzinger, Oscar; Viertl, David; Tsoutsou, Pelagia; Kadi, Linda; Rigotti, Stefania; Zanna, Claudio; Wiedemann, Norbert; Vozenin, Marie-Catherine; Vuagniaux, Grégoire; Bourhis, Jean

    2015-09-01

    Second mitochondria-derived activator of caspase (SMAC)-mimetics are a new class of targeted drugs that specifically induce apoptotic cancer cell death and block pro-survival signaling by antagonizing selected members of the inhibitor of apoptosis protein (IAP) family. The present study was designed to investigate the radiosensitizing effect and optimal sequence of administration of the novel SMAC-mimetic Debio 1143 in vitro and in vivo. Apoptosis, alteration of DNA damage repair (DDR), and tumor necrosis factor-alpha (TNF-α) signaling were examined. In vitro, Debio 1143 displayed anti-proliferative activity and enhanced intrinsic radiation sensitivity in 5/6 head and neck squamous cell carcinoma (HNSCC) cell lines in a synergistic manner. In vivo, Debio 1143 dose-dependently radio-sensitized FaDu and SQ20B xenografts, resulting in complete tumor regression in 8/10 FaDu-xenografted mice at the high dose level. At the molecular level, Debio 1143 combined with radiotherapy (RT) induced enhancement of caspase-3 activity, increase in Annexin V-positive cells and karyopyknosis, and increase in TNF-α mRNA levels. Finally, in a neutralization experiment using a TNF-α-blocking antibody and a caspase inhibitor, it was shown that the radiosensitizing effect of Debio 1143 is mediated by caspases and TNF-α. These results demonstrate that the novel SMAC-mimetic Debio 1143 is a radiosensitizing agent that is worthy of further investigation in clinical trials in combination with radiotherapy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  12. The apolipoprotein-AI mimetic peptide L4F at a modest dose does not attenuate weight gain, inflammation, or atherosclerosis in LDLR-null mice.

    PubMed

    Averill, Michelle M; Kim, Eung Ju; Goodspeed, Leela; Wang, Shari; Subramanian, Savitha; Den Hartigh, Laura J; Tang, Chongren; Ding, Yilei; Reardon, Catherine A; Getz, Godfrey S; Chait, Alan

    2014-01-01

    High density lipoprotein (HDL) cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein) mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/-) model fed a high fat high sucrose with cholesterol (HFHSC) diet. Studies in differentiated 3T3-L1 adipocytes tested whether L4F could inhibit palmitate-induced adipocyte inflammation. In vivo studies used male Ldlr-/- mice fed a HFHSC diet for 12 weeks and were injected daily with L4F (100 µg/mouse) subcutaneously during the last 8 weeks. Wild-type and apoA-I overexpressing Ldlr-/- mice were fed HFHSC diet for 16 weeks. Neither L4F administration nor apoA-I overexpression affected weight gain, total plasma cholesterol or triglycerides in our studies. While pre-treatment of 3T3-L1 adipocytes with either L4F or HDL abolished palmitate-induced cytokine expression in vitro, L4F treatment did not affect circulating or adipose tissue inflammatory markers in vivo. Neither L4F administration nor apoA-I overexpression affected glucose tolerance. ApoA-I overexpression significantly reduced atherosclerotic lesion size, yet L4F treatment did not affect atherosclerosis. Our results suggest that neither L4F (100 µg/day/mouse) nor apoA-I overexpression affects adiposity or insulin resistance in this model. We also were unable to confirm a reduction in atherosclerosis with L4F in our particular model. Further studies on the effect of apoA-I mimetics on atherosclerosis and insulin resistance in a variety of dietary contexts are warranted.

  13. The Apolipoprotein-AI Mimetic Peptide L4F at a Modest Dose Does Not Attenuate Weight Gain, Inflammation, or Atherosclerosis in LDLR-Null Mice

    PubMed Central

    Averill, Michelle M.; Kim, Eung Ju; Goodspeed, Leela; Wang, Shari; Subramanian, Savitha; Den Hartigh, Laura J.; Tang, Chongren; Ding, Yilei; Reardon, Catherine A.; Getz, Godfrey S.; Chait, Alan

    2014-01-01

    Objective High density lipoprotein (HDL) cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein) mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/-) model fed a high fat high sucrose with cholesterol (HFHSC) diet. Methods Studies in differentiated 3T3-L1 adipocytes tested whether L4F could inhibit palmitate-induced adipocyte inflammation. In vivo studies used male Ldlr-/- mice fed a HFHSC diet for 12 weeks and were injected daily with L4F (100 µg/mouse) subcutaneously during the last 8 weeks. Wild-type and apoA-I overexpressing Ldlr-/- mice were fed HFHSC diet for 16 weeks. Results Neither L4F administration nor apoA-I overexpression affected weight gain, total plasma cholesterol or triglycerides in our studies. While pre-treatment of 3T3-L1 adipocytes with either L4F or HDL abolished palmitate-induced cytokine expression in vitro, L4F treatment did not affect circulating or adipose tissue inflammatory markers in vivo. Neither L4F administration nor apoA-I overexpression affected glucose tolerance. ApoA-I overexpression significantly reduced atherosclerotic lesion size, yet L4F treatment did not affect atherosclerosis. Conclusion Our results suggest that neither L4F (100 µg/day/mouse) nor apoA-I overexpression affects adiposity or insulin resistance in this model. We also were unable to confirm a reduction in atherosclerosis with L4F in our particular model. Further studies on the effect of apoA-I mimetics on atherosclerosis and insulin resistance in a variety of dietary contexts are warranted. PMID:25286043

  14. Chemomics-based marker compounds mining and mimetic processing for exploring chemical mechanisms in traditional processing of herbal medicines, a continuous study on Rehmanniae Radix.

    PubMed

    Zhou, Li; Xu, Jin-Di; Zhou, Shan-Shan; Shen, Hong; Mao, Qian; Kong, Ming; Zou, Ye-Ting; Xu, Ya-Yun; Xu, Jun; Li, Song-Lin

    2017-12-29

    Exploring processing chemistry, in particular the chemical transformation mechanisms involved, is a key step to elucidate the scientific basis in traditional processing of herbal medicines. Previously, taking Rehmanniae Radix (RR) as a case study, the holistic chemome (secondary metabolome and glycome) difference between raw and processed RR was revealed by integrating hyphenated chromatographic techniques-based targeted glycomics and untargeted metabolomics. Nevertheless, the complex chemical transformation mechanisms underpinning the holistic chemome variation in RR processing remain to be extensively clarified. As a continuous study, here a novel strategy by combining chemomics-based marker compounds mining and mimetic processing is proposed for further exploring the chemical mechanisms involved in herbal processing. First, the differential marker compounds between raw and processed herbs were rapidly discovered by untargeted chemomics-based mining approach through multivariate statistical analysis of the chemome data obtained by integrated metabolomics and glycomics analysis. Second, the marker compounds were mimetically processed under the simulated physicochemical conditions as in the herb processing, and the final reaction products were chemically characterized by targeted chemomics-based mining approach. Third, the main chemical transformation mechanisms involved were clarified by linking up the original marker compounds and their mimetic processing products. Using this strategy, a set of differential marker compounds including saccharides, glycosides and furfurals in raw and processed RR was rapidly found, and the major chemical mechanisms involved in RR processing were elucidated as stepwise transformations of saccharides (polysaccharides, oligosaccharides and monosaccharides) and glycosides (iridoid glycosides and phenethylalcohol glycosides) into furfurals (glycosylated/non-glycosylated hydroxymethylfurfurals) by deglycosylation and/or dehydration. The

  15. Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D,L-polylactide microparticle formulation.

    PubMed

    Bartolini, D; Piroddi, M; Tidei, C; Giovagnoli, S; Pietrella, D; Manevich, Y; Tew, K D; Giustarini, D; Rossi, R; Townsend, D M; Santi, C; Galli, F

    2015-01-01

    Catalytic properties and cellular effects of the glutathione peroxidase (GPx)-mimetic compound PhSeZnCl or its d,l-lactide polymer microencapsulation form (M-PhSeZnCl) were investigated and compared with the prototypical Se-organic compounds ebselen and diselenide (PhSe)2. PhSeZnCl was confirmed to catalyze the ping-pong reaction of GPx with higher Vmax than ebselen and (PhSe)2, but the catalytic efficiency calculated for the cosubstrates glutathione (GSH) and H2O2, and particularly the high reactivity against thiols (lowest KM for GSH in the series of test molecules), suggested poor biological applicability of PhSeZnCl as a GPx mimetic. Cytotoxicity of PhSeZnCl was demonstrated in various cancer cell lines via increased reactive oxygen species (ROS) generation, depletion of intracellular thiols, and induction of apoptosis. Experiments carried out in GSH S-transferase P (GSTP)-overexpressing K562 human erythroleukemia cells and in GSTP1-1-knockout murine embryonic fibroblasts (MEFs) demonstrated that this cytosolic enzyme represents a preferential target of the redox disturbances produced by this Se-compound with a key role in controlling H2O2 generation and the perturbation of stress/survival kinase signaling. Microencapsulation was adopted as a strategy to control the thiol reactivity and oxidative stress effects of PhSeZnCl, then assessing applications alternative to anticancer. The uptake of this "depowered" GPx-mimetic formulation, which occurred through an endocytosis-like mechanism, resulted in a marked reduction of cytotoxicity. In MCF-7 cells transfected with different allelic variants of GSTP, M-PhSeZnCl lowered the burst of cellular ROS induced by the exposure to extracellular H2O2, and the extent of this effect changed between the GSTP variants. Microencapsulation is a straightforward strategy to mitigate the toxicity of thiol-reactive Se-organic drugs that enhanced the antioxidant and cellular protective effects of PhSeZnCl. A mechanistic linkage of

  16. Substrate-Independent Robust and Heparin-Mimetic Hydrogel Thin Film Coating via Combined LbL Self-Assembly and Mussel-Inspired Post-Cross-linking.

    PubMed

    Ma, Lang; Cheng, Chong; He, Chao; Nie, Chuanxiong; Deng, Jie; Sun, Shudong; Zhao, Changsheng

    2015-12-02

    In this work, we designed a robust and heparin-mimetic hydrogel thin film coating via combined layer-by-layer (LbL) self-assembly and mussel-inspired post-cross-linking. Dopamine-grafted heparin-like/-mimetic polymers (DA-g-HepLP) with abundant carboxylic and sulfonic groups were synthesized by the conjugation of adhesive molecule, DA, which exhibited substrate-independent adhesive affinity to various solid surfaces because of the formation of irreversible covalent bonds. The hydrogel thin film coated substrates were prepared by a three-step reaction: First, the substrates were coated with DA-g-HepLP to generate negatively charged surfaces. Then, multilayers were obtained via LbL coating of chitosan and the DA-g-HepLP. Finally, the noncovalent multilayers were oxidatively cross-linked by NaIO4. Surface ATR-FTIR and XPS spectra confirmed the successful fabrication of the hydrogel thin film coatings onto membrane substrates; SEM images revealed that the substrate-independent coatings owned 3D porous morphology. The soaking tests in highly alkaline, acid, and concentrated salt solutions indicated that the cross-linked hydrogel thin film coatings owned high chemical resistance. In comparison, the soaking tests in physiological solution indicated that the cross-linked hydrogel coatings owned excellent long-term stability. The live/dead cell staining and morphology observations of the adhered cells revealed that the heparin-mimetic hydrogel thin film coated substrates had low cell toxicity and high promotion ability for cell proliferation. Furthermore, systematic in vitro investigations of protein adsorption, platelet adhesion, blood clotting, and blood-related complement activation confirmed that the hydrogel film coated substrates showed excellent hemocompatibility. Both the results of inhibition zone and bactericidal activity indicated that the gentamycin sulfate loaded hydrogel thin films had significant inhibition capability toward both Escherichia coli and

  17. Platelet anti-aggregatory effects of coumarins from the roots of Angelica genuflexa and A. gigas.

    PubMed

    Lee, Yong Yook; Lee, Sanghyun; Jin, Jing Ling; Yun-Choi, Hye Sook

    2003-09-01

    Five coumarins, isoimperatorin (1), pabulenol (2), isooxypeucedanin (3), oxypeucedanin hydrate (4) and osthol (5) were isolated from the MeOH extract of Angelica genuflexa in the course of searching for anti-platelet and anti-coagulant components from plants. Pabulenol (2) was isolated from A. genuflexa for the first time. The five compounds isolated from A. genuflexa, together with decursinol angelate (6), decursin (7) and nodakenin (8) from A. gigas were evaluated for their effects on platelet aggregation and blood coagulation. Compounds 2, 5, 6 and 7 were observed to be either equally effective or 2-4 times more inhibitory than ASA in both arachidonic acid and U46619 (TXA2 mimetic) induced platelet aggregations.

  18. Coronary vasoconstrictor effect of ghrelin is not mediated by growth hormone secretagogue receptor 1a type in dogs.

    PubMed

    Sax, Balazs; Nadasy, Gyorgy L; Turi, Katalin; Hirschberg, Kristof; Furjesz, Dora; Nagy, Andrea; Merkely, Bela; Szabo, Gabor; Monos, Emil; Kekesi, Violetta

    2011-02-01

    Ghrelin (GHR) is a recently discovered endocrine regulatory peptide of gastrointestinal origin with multiple functions including cardiovascular effects. However, contradictory data are available on the vascular actions of GHR in different organs and species. The aim of this study was to characterize the direct effect of the peptide on the canine coronary bed and to evaluate the role of the growth hormone secretagogue receptor (GHS-R) in the effect of GHR on coronary arterioles. The presence of GHS-R1a and 1b subtypes in canine coronary arterioles was investigated using Western blotting and immunohistochemistry. Responses of coronary arterioles with spontaneous and elevated vascular tone (the latter evoked by the thromboxane mimetic agent U46619, 10(-7)-10(-6)mol/l) to GHR (10(-9)-3×10(-7)nmol/l) were recorded by video-microscopy as changes of vessel diameter. Positive immunostaining for both GHS-R subtypes was found in the wall of intramural arterioles. The microarteriographic study results showed that GHR alone could not elicit any significant effect on vessel diameter of arterioles with spontaneous tone. However, when vascular smooth muscle was preconstricted by the thromboxane mimetic agent U46619, administration of GHR induced further constriction (+31±9% increase in contraction p<0.01). This was not abolished by the specific blockade of GHS-R1a by d-Lys(3)-GHRP-6 (5×10(-6)mol/l). The results suggest that GHR induces tone-dependent constriction of canine coronary arterioles which is mediated by a receptor other than GHS-R1a. Copyright © 2010 Elsevier Inc. All rights reserved.

  19. Cellular Fates of Manganese(II) Pentaazamacrocyclic Superoxide Dismutase (SOD) Mimetics: Fluorescently Labeled MnSOD Mimetics, X-ray Absorption Spectroscopy, and X-ray Fluorescence Microscopy Studies.

    PubMed

    Weekley, Claire M; Kenkel, Isabell; Lippert, Rainer; Wei, Shengwei; Lieb, Dominik; Cranwell, Tiffanny; Wedding, Jason L; Zillmann, Annika S; Rohr, Robin; Filipovic, Milos R; Ivanović-Burmazović, Ivana; Harris, Hugh H

    2017-06-05

    Manganese(II) pentaazamacrocyclic complexes (MnPAMs) can act as small-molecule mimics of manganese superoxide dismutase (MnSOD) with potential therapeutic application in conditions linked to oxidative stress. Previously, the in vitro mechanism of action has been determined, their activity has been demonstrated in cells, and some representatives of this class of MnSOD mimetics have entered clinical trials. However, MnPAM uptake, distribution, and metabolism in cells are largely unknown. Therefore, we have used X-ray fluorescence microscopy (XFM) and X-ray absorption spectroscopy (XAS) to study the cellular fate of a number of MnPAMs. We have also synthesized and characterized fluorescently labeled (pyrene and rhodamine) manganese(II) pyane [manganese(II) trans-2,13-dimethyl-3,6,9,12,18-pentaazabicyclo[12.3.1]octadeca-1(18),14,16-triene] derivatives and investigated their utility for cellular imaging of MnPAMs. Their SOD activity was determined via a direct stopped-flow technique. XFM experiments show that treatment with amine-based manganese(II) pyane type pentaazamacrocycles leads to a 10-100-fold increase in the overall cellular manganese levels compared to the physiological levels of manganese in control cells. In treated cells in general, manganese was distributed throughout the cell body, with a couple of notable exceptions. The lipophilicity of the MnPAMs, examined by partitioning in octanol-buffer system, was a good predictor of the relative cellular manganese levels. Analysis of the XAS data of treated cells revealed that some fraction of amine-based MnPAMs taken up by the cells remained intact, with the rest transformed into SOD-active manganese(II) phosphate. Higher phosphate binding constants, determined from the effect of the phosphate concentration on in vitro SOD activity, were associated with more extensive metabolism of the amine-based MnPAMs to manganese(II) phosphate. In contrast, the imine-based manganese(II) pydiene complex that is prone to

  20. Ultratrace Naked-Eye Colorimetric Detection of Hg2+in Wastewater and Serum Utilizing Mercury-Stimulated Peroxidase Mimetic Activity of Reduced Graphene Oxide-PEI-Pd Nanohybrids.

    PubMed

    Zhang, Shouting; Zhang, Dongxu; Zhang, Xuehong; Shang, Denghui; Xue, Zhonghua; Shan, Duoliang; Lu, Xiaoquan

    2017-03-21

    Herein, we developed a general strategy for rapid, highly selective, and ultratrace naked-eye colorimetric detection of Hg 2+ in aqueous solutions. Two dimensional rGO/PEI/Pd nanohybrids, where rGO, PEI, and Pd were referred to as reduced graphene oxide, polyethylenimine, and Pd nanoparticles, respectively, were synthesized and used as mimetic peroxidase for selective and ultrasensitive detection of Hg 2+ in water and human serum samples. In the presence of mercury ions, the peroxidase mimetic activity of rGO/PEI/Pd nanohybrids was found to be stimulated and enhanced significantly, which promoted the effective oxidation and color change of 3,3',5,5'-tetramethylbenzidine (TMB) in solution to dark blue that was detected by the naked-eye and the absorption spectroscopic method. The proposed sensing strategy coupled with spectroscopic detection method showed an ultralow detection limit of 0.39 nM for Hg 2+ in ddH 2 O and ∼1 nM in wastewater as well as serum samples, respectively. On the basis of the colorimetric assay, a minimum concentration of ∼10 nM for Hg 2+ in wastewater and human serum can be detected with the naked-eye. The naked-eye-based colorimetric assay for sensitive and selective detection of mercury is expected to hold huge potentials in applications such as environmental monitoring, clinical diagnosis, and pharmaceutical analysis.

  1. Potent human glutaminyl cyclase inhibitors as potential anti-Alzheimer's agents: Structure-activity relationship study of Arg-mimetic region.

    PubMed

    Ngo, Van T H; Hoang, Van-Hai; Tran, Phuong-Thao; Ann, Jihyae; Cui, Minghua; Park, Gyungseo; Choi, Sun; Lee, Jiyoun; Kim, Hee; Ha, Hee-Jin; Choi, Kwanghyun; Kim, Young-Ho; Lee, Jeewoo

    2018-03-01

    Pyroglutamate-modified amyloid β peptides (pGlu-Aβ) are highly neurotoxic and promote the formation of amyloid plaques. The pGlu-Aβ peptides are generated by glutaminyl cyclase (QC), and recent clinical studies indicate that QC represents an alternative therapeutic target to treat Alzheimer's disease (AD). We have previously developed a series of QC inhibitors with an extended pharmacophoric scaffold, termed the Arg-mimetic D-region. In the present study, we focused on the structure activity relationship (SAR) of analogues with modifications in the D-region and evaluated their biological activity. Most compounds in this series exhibited potent activity in vitro, and our SAR analysis and the molecular docking studies identified compound 202 as a potential candidate because it forms an additional hydrophobic interaction in the hQC active site. Overall, our study provides valuable insights into the Arg-mimetic pharmacophore that will guide the design of novel QC inhibitors as potential treatments for AD. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Coating of Bio-mimetic Minerals-Substituted Hydroxyapatite on Surgical Grade Stainless Steel 316L by Electrophoretic Deposition for Hard tissue Applications

    NASA Astrophysics Data System (ADS)

    Govindaraj, Dharman; Rajan, Mariappan

    2018-02-01

    Third-era bio-implant materials intend to empower particular live cell reactions at the atomic level, these materials represented with a resorbable and biocompatibility that bodies recuperate once they have been embedded. Necessitate to decrease expenses in public health services has required the utilization of surgical grade stainless steel (SS 316L) as the most inexpensive choice for orthodontic and orthopaedic implants. 316L SS is one of the broadly used implant biomaterials in orthodontic and orthopaedic surgeries. Yet, frequently those discharge for toxic metal ions is confirm from the implants and hence a second surgery is required will remove those implant material. One approach to managing the discharge of toxic metal ions is to coat the implant substance with bio-mimetic minerals in hydroxyapatite (HA). Bio-mimetic minerals such as magnesium (Mg), strontium (Sr), also zinc (Zn) were revealed with animate bone growth furthermore restrain bone resorption both in vitro and in vivo. The present work deals with the electrophoretic deposition (EPD) for multi minerals substituted hydroxyapatite (M-HA) on the surface treated 316L SS under distinctive temperatures (27°C, (room temperature), 60 and 80°C). The resultant coatings were characterized by FT-IR, XRD, SEM-EDX, adhesion strength and leach out analysis.

  3. Modeling of Arylamide Helix Mimetics in the p53 Peptide Binding Site of hDM2 Suggests Parallel and Anti-Parallel Conformations Are Both Stable

    PubMed Central

    Fuller, Jonathan C.; Jackson, Richard M.; Edwards, Thomas A.; Wilson, Andrew J.; Shirts, Michael R.

    2012-01-01

    The design of novel α-helix mimetic inhibitors of protein-protein interactions is of interest to pharmaceuticals and chemical genetics researchers as these inhibitors provide a chemical scaffold presenting side chains in the same geometry as an α-helix. This conformational arrangement allows the design of high affinity inhibitors mimicking known peptide sequences binding specific protein substrates. We show that GAFF and AutoDock potentials do not properly capture the conformational preferences of α-helix mimetics based on arylamide oligomers and identify alternate parameters matching solution NMR data and suitable for molecular dynamics simulation of arylamide compounds. Results from both docking and molecular dynamics simulations are consistent with the arylamides binding in the p53 peptide binding pocket. Simulations of arylamides in the p53 binding pocket of hDM2 are consistent with binding, exhibiting similar structural dynamics in the pocket as simulations of known hDM2 binders Nutlin-2 and a benzodiazepinedione compound. Arylamide conformations converge towards the same region of the binding pocket on the 20 ns time scale, and most, though not all dihedrals in the binding pocket are well sampled on this timescale. We show that there are two putative classes of binding modes for arylamide compounds supported equally by the modeling evidence. In the first, the arylamide compound lies parallel to the observed p53 helix. In the second class, not previously identified or proposed, the arylamide compound lies anti-parallel to the p53 helix. PMID:22916232

  4. Significant In Vivo Anti-Inflammatory Activity of Pytren4Q-Mn a Superoxide Dismutase 2 (SOD2) Mimetic Scorpiand-Like Mn (II) Complex

    PubMed Central

    Serena, Carolina; Calvo, Enrique; Clares, Mari Paz; Diaz, María Luisa; Chicote, Javier U.; Beltrán-Debon, Raúl; Fontova, Ramón; Rodriguez, Alejandro; García-España, Enrique; García-España, Antonio

    2015-01-01

    Background The clinical use of purified SOD enzymes has strong limitations due to their large molecular size, high production cost and immunogenicity. These limitations could be compensated by using instead synthetic SOD mimetic compounds of low molecular weight. Background/Methodology We have recently reported that two SOD mimetic compounds, the MnII complexes of the polyamines Pytren2Q and Pytren4Q, displayed high antioxidant activity in bacteria and yeast. Since frequently molecules with antioxidant properties or free-radical scavengers also have anti-inflammatory properties we have assessed the anti-inflammatory potential of Pytren2Q and Pytren4Q MnII complexes, in cultured macrophages and in a murine model of inflammation, by measuring the degree of protection they could provide against the cellular injury produced by lipopolisacharide, a bacterial endotoxin. Principal Findings In this report we show that the MnII complex of Pytren4Q but not that of Pytren2Q effectively protected human cultured THP-1 macrophages and whole mice from the inflammatory effects produced by LPS. These results obtained with two molecules that are isomers highlight the importance of gathering experimental data from animal models of disease in assessing the potential of candidate molecules. Conclusion/Significance The effective anti-inflammatory activity of the MnII complex of Pytren4Q in addition to its low toxicity, water solubility and ease of production would suggest it is worth taking into consideration for future pharmacological studies. PMID:25742129

  5. Highly stable hexacoordinated nonoxidovanadium(IV) complexes of sterically constrained ligands: syntheses, structure, and study of antiproliferative and insulin mimetic activity.

    PubMed

    Dash, Subhashree P; Pasayat, Sagarika; Bhakat, Saswati; Roy, Satabdi; Dinda, Rupam; Tiekink, Edward R T; Mukhopadhyay, Subhadip; Bhutia, Sujit K; Hardikar, Manasi R; Joshi, Bimba N; Patil, Yogesh P; Nethaji, M

    2013-12-16

    Three highly stable, hexacoordinated nonoxidovanadium(IV), V(IV)(L)2, complexes (1-3) have been isolated and structurally characterized with tridentate aroylhydrazonates containing ONO donor atoms. All the complexes are stable in the open air in the solid state as well as in solution, a phenomenon rarely observed in nonoxidovanadium(IV) complexes. The complexes have good solubility in organic solvents, permitting electrochemical and various spectroscopic investigations. The existence of nonoxidovanadium(IV) complexes was confirmed by elemental analysis, ESI mass spectroscopy, cyclic voltammetry, EPR, and magnetic susceptibility measurements. X-ray crystallography showed the N3O3 donor set to define a trigonal prismatic geometry in each case. All the complexes show in vitro insulin mimetic activity against insulin responsive L6 myoblast cells, with complex 3 being the most potent, which is comparable to insulin at the complex concentration of 4 μM, while the others have moderate insulin mimetic activity. In addition, the in vitro antiproliferative activity of complexes 1-3 against the HeLa cell line was assayed. The cytotoxicity of the complexes is affected by the various functional groups attached to the bezoylhydrazone derivative and 2 showed considerable antiproliferative activity compared to the most commonly used chemotherapeutic drugs.

  6. BST-2 Expression Modulates Small CD4-Mimetic Sensitization of HIV-1-Infected Cells to Antibody-Dependent Cellular Cytotoxicity

    PubMed Central

    Prévost, Jérémie; von Bredow, Benjamin; Ding, Shilei; Brassard, Nathalie; Medjahed, Halima; Coutu, Mathieu; Melillo, Bruno; Bibollet-Ruche, Frédéric; Hahn, Beatrice H.; Kaufmann, Daniel E.; Smith, Amos B.; Sodroski, Joseph; Sauter, Daniel; Kirchhoff, Frank; Gee, Katrina; Neil, Stuart J.; Evans, David T.

    2017-01-01

    ABSTRACT Antibodies recognizing conserved CD4-induced (CD4i) epitopes on human immunodeficiency virus type 1 (HIV-1) Env and able to mediate antibody-dependent cellular cytotoxicity (ADCC) have been shown to be present in sera from most HIV-1-infected individuals. These antibodies preferentially recognize Env in its CD4-bound conformation. CD4 downregulation by Nef and Vpu dramatically reduces exposure of CD4i HIV-1 Env epitopes and therefore reduce the susceptibility of HIV-1-infected cells to ADCC mediated by HIV-positive (HIV+) sera. Importantly, this mechanism of immune evasion can be circumvented with small-molecule CD4 mimetics (CD4mc) that are able to transition Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC mediated by HIV+ sera. However, HIV-1 developed additional mechanisms to avoid ADCC, including Vpu-mediated BST-2 antagonism, which decreases the overall amount of Env present at the cell surface. Accordingly, BST-2 upregulation in response to alpha interferon (IFN-α) was shown to increase the susceptibility of HIV-1-infected cells to ADCC despite the activity of Vpu. Here we show that BST-2 upregulation by IFN-β and interleukin-27 (IL-27) also increases the surface expression of Env and thus boosts the ability of CD4mc to sensitize HIV-1-infected cells to ADCC by sera from HIV-1-infected individuals. IMPORTANCE HIV-1 evolved sophisticated strategies to conceal Env epitopes from ADCC-mediating antibodies present in HIV+ sera. Vpu-mediated BST-2 downregulation was shown to decrease ADCC responses by limiting the amount of Env present at the cell surface. This effect of Vpu was shown to be attenuated by IFN-α treatment. Here we show that in addition to IFN-α, IFN-β and IL-27 also affect Vpu-mediated BST-2 downregulation and greatly enhance ADCC responses against HIV-1-infected cells in the presence of CD4mc. These findings may inform strategies aimed at HIV prevention and eradication. PMID:28331088

  7. Potent and selective small-molecule inhibitors of cIAP1/2 proteins reveal that the binding of Smac mimetics to XIAP BIR3 is not required for their effective induction of cell death in tumor cells.

    PubMed

    Sun, Haiying; Lu, Jianfeng; Liu, Liu; Yang, Chao-Yie; Wang, Shaomeng

    2014-04-18

    Cellular inhibitor of apoptosis protein 1 and 2 (cIAP1/2) and X-linked inhibitor of apoptosis protein (XIAP) are key apoptosis regulators and promising new cancer therapeutic targets. This study describes a set of non-peptide, small-molecule Smac (second mitochondria-derived activator of caspases) mimetics that are selective inhibitors of cIAP1/2 over XIAP. The most potent and most selective compounds bind to cIAP1/2 with affinities in the low nanomolar range and show >1,000-fold selectivity for cIAP1 over XIAP. These selective cIAP inhibitors effectively induce degradation of the cIAP1 protein in cancer cells at low nanomolar concentrations and do not antagonize XIAP in a cell-free functional assay. They potently inhibit cell growth and effectively induce apoptosis at low nanomolar concentrations in cancer cells with a mechanism of action similar to that of other known Smac mimetics. Our study shows that binding of Smac mimetics to XIAP BIR3 is not required for effective induction of apoptosis in tumor cells by Smac mimetics. These potent and highly selective cIAP1/2 inhibitors are powerful tools in the investigation of the role of these IAP proteins in the regulation of apoptosis and other cellular processes.

  8. Spaceflight on the Bion-M1 biosatellite alters cerebral artery vasomotor and mechanical properties in mice.

    PubMed

    Sofronova, Svetlana I; Tarasova, Olga S; Gaynullina, Dina; Borzykh, Anna A; Behnke, Bradley J; Stabley, John N; McCullough, Danielle J; Maraj, Joshua J; Hanna, Mina; Muller-Delp, Judy M; Vinogradova, Olga L; Delp, Michael D

    2015-04-01

    Conditions during spaceflight, such as the loss of the head-to-foot gravity vector, are thought to potentially alter cerebral blood flow and vascular resistance. The purpose of the present study was to determine the effects of long-term spaceflight on the functional, mechanical, and structural properties of cerebral arteries. Male C57BL/6N mice were flown 30 days in a Bion-M1 biosatellite. Basilar arteries isolated from spaceflight (SF) (n = 6), habitat control (HC) (n = 6), and vivarium control (VC) (n = 16) mice were used for in vitro functional and mechanical testing and histological structural analysis. The results demonstrate that vasoconstriction elicited through a voltage-gated Ca(2+) mechanism (30-80 mM KCl) and thromboxane A2 receptors (10(-8) - 3 × 10(-5) M U46619) are lower in cerebral arteries from SF mice. Inhibition of Rho-kinase activity (1 μM Y27632) abolished group differences in U46619-evoked contractions. Endothelium-dependent vasodilation elicited by acetylcholine (10 μM, 2 μM U46619 preconstriction) was virtually absent in cerebral arteries from SF mice. The pressure-diameter relation was lower in arteries from SF mice relative to that in HC mice, which was not related to differences in the extracellular matrix protein elastin or collagen content or the elastin/collagen ratio in the basilar arteries. Diameter, medial wall thickness, and medial cross-sectional area of unpressurized basilar arteries were not different among groups. These results suggest that the microgravity-induced attenuation of both vasoconstrictor and vasodilator properties may limit the range of vascular control of cerebral perfusion or impair the distribution of brain blood flow during periods of stress. Copyright © 2015 the American Physiological Society.

  9. Spaceflight on the Bion-M1 biosatellite alters cerebral artery vasomotor and mechanical properties in mice

    PubMed Central

    Sofronova, Svetlana I.; Tarasova, Olga S.; Gaynullina, Dina; Borzykh, Anna A.; Behnke, Bradley J.; Stabley, John N.; McCullough, Danielle J.; Maraj, Joshua J.; Hanna, Mina; Muller-Delp, Judy M.; Vinogradova, Olga L.

    2015-01-01

    Conditions during spaceflight, such as the loss of the head-to-foot gravity vector, are thought to potentially alter cerebral blood flow and vascular resistance. The purpose of the present study was to determine the effects of long-term spaceflight on the functional, mechanical, and structural properties of cerebral arteries. Male C57BL/6N mice were flown 30 days in a Bion-M1 biosatellite. Basilar arteries isolated from spaceflight (SF) (n = 6), habitat control (HC) (n = 6), and vivarium control (VC) (n = 16) mice were used for in vitro functional and mechanical testing and histological structural analysis. The results demonstrate that vasoconstriction elicited through a voltage-gated Ca2+ mechanism (30–80 mM KCl) and thromboxane A2 receptors (10−8 − 3 × 10−5 M U46619) are lower in cerebral arteries from SF mice. Inhibition of Rho-kinase activity (1 μM Y27632) abolished group differences in U46619-evoked contractions. Endothelium-dependent vasodilation elicited by acetylcholine (10 μM, 2 μM U46619 preconstriction) was virtually absent in cerebral arteries from SF mice. The pressure-diameter relation was lower in arteries from SF mice relative to that in HC mice, which was not related to differences in the extracellular matrix protein elastin or collagen content or the elastin/collagen ratio in the basilar arteries. Diameter, medial wall thickness, and medial cross-sectional area of unpressurized basilar arteries were not different among groups. These results suggest that the microgravity-induced attenuation of both vasoconstrictor and vasodilator properties may limit the range of vascular control of cerebral perfusion or impair the distribution of brain blood flow during periods of stress. PMID:25593287

  10. Functional expression of human serum albumin-tandem thrombopoietin mimetic peptide fusion protein as a novel thrombopoietin analog in Pichia pastoris.

    PubMed

    Wang, Meizhu; Zhi, Dejuan; Xian, Jun; Ru, Yi; Wei, Suzhen; Wang, Na; Liu, Yiyao; Wang, Haiqing; Pei, Yuejuan; Song, Meijuan; Li, Yang; Li, Hongyu

    2016-05-01

    To develop a novel thrombopoietin (TPO) analog by fusing the tandem TPO mimetic peptide (TMP-TMP) to human serum albumin (HSA) and performing functional expression of recombinant fusion protein HSA-TMP-TMP. After optimizing the fusion orientation in shake-flask culture, HSA-TMP-TMP was expressed at 0.4 g/l in Pichia pastoris grown in a 20 l bioreactor, during which pH was controlled at 5 by addition of NH4OH and citric acid. The fusion protein significantly activated signal transducer and activator of transcription-mediated transcription in TPO receptor-dependent manner, which was demonstrated by a luciferase reporter assay. Following subcutaneous administration, HSA-TMP-TMP effectively stimulated the platelet production in healthy mice in a dose-dependent manner. Successful expression of HSA-TMP-TMP fusion protein in P. pastoris was achieved and the recombinant HSA-TMP-TMP is a promising TPO analog.

  11. Insight into the mechanism revealing the peroxidase mimetic catalytic activity of quaternary CuZnFeS nanocrystals: colorimetric biosensing of hydrogen peroxide and glucose

    NASA Astrophysics Data System (ADS)

    Dalui, Amit; Pradhan, Bapi; Thupakula, Umamahesh; Khan, Ali Hossain; Kumar, Gundam Sandeep; Ghosh, Tanmay; Satpati, Biswarup; Acharya, Somobrata

    2015-05-01

    Artificial enzyme mimetics have attracted immense interest recently because natural enzymes undergo easy denaturation under environmental conditions restricting practical usefulness. We report for the first time chalcopyrite CuZnFeS (CZIS) alloyed nanocrystals (NCs) as novel biomimetic catalysts with efficient intrinsic peroxidase-like activity. Novel peroxidase activities of CZIS NCs have been evaluated by catalytic oxidation of the peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of hydrogen peroxide (H2O2). CZIS NCs demonstrate the synergistic effect of elemental composition and photoactivity towards peroxidase-like activity. The quaternary CZIS NCs show enhanced intrinsic peroxidase-like activity compared to the binary NCs with the same constituent elements. Intrinsic peroxidase-like activity has been correlated with the energy band position of CZIS NCs extracted using scanning tunneling spectroscopy and ultraviolet photoelectron spectroscopy. Kinetic analyses indicate Michaelis-Menten enzyme kinetic model catalytic behavior describing the rate of the enzymatic reaction by correlating the reaction rate with substrate concentration. Typical color reactions arising from the catalytic oxidation of TMB over CZIS NCs with H2O2 have been utilized to establish a simple and sensitive colorimetric assay for detection of H2O2 and glucose. CZIS NCs are recyclable catalysts showing high efficiency in multiple uses. Our study may open up the possibility of designing new photoactive multi-component alloyed NCs as enzyme mimetics in biotechnology applications.Artificial enzyme mimetics have attracted immense interest recently because natural enzymes undergo easy denaturation under environmental conditions restricting practical usefulness. We report for the first time chalcopyrite CuZnFeS (CZIS) alloyed nanocrystals (NCs) as novel biomimetic catalysts with efficient intrinsic peroxidase-like activity. Novel peroxidase activities of CZIS NCs have been

  12. Test-Retest Reliability and Agreement Between In-Person and Video Assessment of Facial Mimetic Function Using the eFACE Facial Grading System.

    PubMed

    Banks, Caroline A; Jowett, Nate; Hadlock, Tessa A

    2017-05-01

    Use of a robust high-resolution instrument for grading of facial symmetry would enhance reporting the outcomes of facial reanimation interventions. The eFACE is one such tool. To determine test-retest reliability of the eFACE tool over time and agreement between eFACE assessments made in person vs those made using video of facial mimetic function. A prospective observational study was conducted among 75 consecutive patients with varying degrees of facial palsy who presented between July 1 and December 31, 2014, to an academic tertiary referral hospital. Facial symmetry of all patients was graded in person and via standardized photographic and video documentation of facial mimetic function at the initial visit. Three months after initial presentation, eFACE scores were reassessed by the same raters using the videos of facial mimetic function documented at the initial visit. Individual and subset eFACE scores assessed by 2 facial reanimation surgeons. Among the 75 patients in the study (mean [SD] age, 48.18 [16.60] years; 30 men and 45 women), agreement between in-person and video assessments of facial function using the eFACE scale was excellent (static subset score: mean difference, 0.19; 95% CI, -1.51 to 1.88; P = .83; intraclass correlation coefficient [ICC], 0.85; 95% CI, 0.80 to 0.89; dynamic subset score: mean difference, -0.51; 95% CI, -1.72 to 0.71; P = .41; ICC, 0.96; 95% CI, 0.94 to 0.97; synkinesis subset score: mean difference, -1.14; 95% CI, -2.87 to 0.59; P = .20; ICC, 0.90; 95% CI, 0.86 to 0.93; and composite score: mean difference, -0.41; 95% CI, -1.30 to 0.47; P = .36; ICC, 0.94; 95% CI, 0.92 to 0.96). Agreement between repeated eFACE assessments of video of facial function was excellent (static subset score: ICC, 0.93; 95% CI, 0.87 to 0.96; dynamic subset score: ICC, 0.88; 95% CI, 0.80 to 0.94; synkinesis subset score: ICC, 0.92; 95% CI, 0.86 to 0.96; and composite score: ICC, 0.96; 95% CI, 0.93 to 0.98). Strong agreement exists

  13. Modeling the capture rate by a radially oscillating spherical bubble. A bio-mimetic model for studying the mechanically-mediated uptake by cells

    NASA Astrophysics Data System (ADS)

    Raudino, Antonio; Raciti, Domenica; Grassi, Antonio

    2016-11-01

    The surface of living cells constitutes a dynamic environment submitted to complex oscillatory motions. Oscillations may modify the uptake of incoming molecules. In this study we explored a bio-mimetic system formed by oscillating bubbles suspended in a sea of randomly distributed diffusants. We investigated by a time-dependent Fokker-Planck equation the effect of the periodic motions on the adsorption of a diffusant onto the moving bubble surface. We introduced both direct interactions between the diffusant and the fluctuating surface and indirect interactions due to the hydrodynamic motions around a vibrating surface. Results are expressed in terms of oscillation frequencies and amplitudes. An overall reduction of the bound diffusant at the bubble surface was observed.

  14. Template synthesis, spectroscopic characterization and preliminary insulin-mimetic activity of oxovanadium(IV) complexes with N2O2 diazadioxa macrocycles

    NASA Astrophysics Data System (ADS)

    Sharma, M. L.; Sengupta, S. K.; Pandey, O. P.

    A new series of diazadioxa oxovanadium(IV) macrocyclic complexes of type [VO(mac)]SO4 have been synthesized via the condensation reaction of a 3-(phenyl/substituted phenyl)-4-amino-5-hydrazino-1,2,4-triazole (H2L) with salicylaldehyde/2-hydroxyacetophenone and 1,4-dibromobutane in the presence of oxovanadium(IV) sulfate in ethanol. All the newly synthesized compounds were characterized on the basis of elemental analyses, conductance measurements, magnetic properties, spectral (UV-Vis, IR, EPR) and XRD studies. The particle size of the complexes has been calculated from XRD spectra using Debye-Scherrer formula and these are found to be in 31-32 nm range. The efficacy of two macrocyclic complexes was also studied in streptozotocin-induced diabetic rats over a period of 30 days. The administration of these complexes in diabetic rats reversed the diabetic effect due to their insulin-mimetic effects.

  15. Phosphoinositide 3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt's lymphoma cells to BH3 mimetics.

    PubMed

    Spender, Lindsay C; Inman, Gareth J

    2012-03-01

    Burkitt's lymphoma (BL), driven by translocation and overexpression of the c-MYC gene, is an aggressive, highly proliferative lymphoma, and novel therapeutic strategies are required to overcome drug resistance following conventional treatments. The importance of the prosurvival BCL-2 family member BCL-X(L) in BL cell survival suggests that antagonistic BH3-mimetic compounds may have therapeutic potential. Here, we show that treatment of BL cell lines with ABT-737 induces caspase-3/7 activation and apoptosis with varying potency. Using selective inhibitors, we identify phosphoinositide 3-kinase (PI3K) as a proproliferative/survival pathway in BL cells and investigate the potential of combined pharmacologic inhibition of both the BCL-2 family and PI3K signaling pathway. PI3K/AKT inhibition and ABT-737 treatment induced synergistic caspase activation, augmented BL cell apoptosis, and rendered chemoresistant cells sensitive. Targeting mTORC1/2 with PP242 was also effective, either as a monotherapy or, more generally, in combination with ABT-737. The combined use of a dual specificity PI3K/mTOR inhibitor (PI 103) with ABT-737 proved highly efficacious. PI 103 treatment of BL cells was associated with an increase in BIM/MCL-1 expression ratios and loss of c-MYC expression. Furthermore, blocking c-MYC function using the inhibitor 10058-F4 also induced apoptosis synergistically with ABT-737, suggesting that maintenance of expression of BCL-2 family members and/or c-MYC by the PI3K/AKT/mTOR pathway could contribute to BL cell survival and resistance to ABT-737. The combined use of BH3 mimetics and selective mTORC1/2 inhibitors may therefore be a useful novel therapeutic approach for the treatment of B-cell malignancy, including chemoresistant lymphomas.

  16. Phosphoinositide-3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt’s Lymphoma cells to BH3-mimetics

    PubMed Central

    Spender, Lindsay C; Inman, Gareth J

    2012-01-01

    Burkitt’s lymphoma (BL), driven by translocation and over-expression of the c-MYC gene, is an aggressive, highly proliferative lymphoma and novel therapeutic strategies are required to overcome drug resistance following conventional treatments. The importance of the pro-survival BCL-2 family member BCL-XL in BL cell survival suggests that antagonistic BH3-mimetic compounds may have therapeutic potential. Here we show that treatment of BL cell lines with ABT-737 induces caspase-3/7 activation and apoptosis with varying potency. Using selective inhibitors, we identify phosphoinositide-3-kinase (PI3K) as a pro-proliferative/survival pathway in BL cells and investigate the potential of combined pharmacological inhibition of both the BCL-2 family and PI3K signaling pathway. PI3K/AKT inhibition and ABT-737 treatment induced synergistic caspase activation, augmented BL cell apoptosis and rendered chemo-resistant cells sensitive. Targeting mTORC1/2 with PP242 was also effective, either as a monotherapy or, more generally, in combination with ABT-737. The combined use of a dual specificity PI3K/mTOR inhibitor (PI 103) with ABT-737 proved highly efficacious. PI 103 treatment of BL cells was associated with an increase in BIM/MCL-1 expression ratios and loss of c-MYC expression. Furthermore, blocking c-MYC function using the inhibitor 10058-F4 also induced apoptosis synergistically with ABT-737, suggesting that maintenance of expression of BCL-2 family members and/or c-MYC by the PI3K/AKT/mTOR pathway could contribute to BL cell survival and resistance to ABT-737. The combined use of BH3-mimetics and selective mTORC1/2 inhibitors may therefore be a useful novel therapeutic approach for the treatment of B-cell malignancy, including chemo-resistant lymphomas. PMID:22241218

  17. d-Allulose, a stereoisomer of d-fructose, extends Caenorhabditis elegans lifespan through a dietary restriction mechanism: A new candidate dietary restriction mimetic.

    PubMed

    Shintani, Tomoya; Sakoguchi, Hirofumi; Yoshihara, Akihide; Izumori, Ken; Sato, Masashi

    2017-12-02

    Dietary restriction (DR) is an effective intervention known to increase lifespan in a wide variety of organisms. DR also delays the onset of aging-associated diseases. DR mimetics, compounds that can mimic the effects of DR, have been intensively explored. d-Allulose (d-Alu), the C3-epimer of d-fructose, is a rare sugar that has various health benefits, including anti-hyperglycemia and anti-obesity effects. Here, we report that d-Alu increased the lifespan of Caenorhabditis elegans both under monoxenic and axenic culture conditions. d-Alu did not further extend the lifespan of the long-lived DR model eat-2 mutant, strongly indicating that the effect is related to DR. However, d-Alu did not reduce the food intake of wild-type C. elegans. To explore the mechanisms of the d-Alu longevity effect, we examined the lifespan of d-Alu-treated mutants deficient for nutrient sensing pathway-related genes daf-16, sir-2.1, aak-2, and skn-1. As a result, d-Alu increased the lifespan of the daf-16, sir-2.1, and skn-1 mutants, but not the aak-2 mutant, indicating that the lifespan extension was dependent on the energy sensor, AMP-activated protein kinase (AMPK). d-Alu also enhanced the mRNA expression and enzyme activities of superoxide dismutase (SOD) and catalase. From these findings, we conclude that d-Alu extends lifespan by increasing oxidative stress resistance through a DR mechanism, making it a candidate DR mimetic. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. The SMAC mimetic BV6 induces cell death and sensitizes different cell lines to TNF-α and TRAIL-induced apoptosis.

    PubMed

    El-Mesery, Mohamed; Shaker, Mohamed E; Elgaml, Abdelaziz

    2016-12-01

    The inhibitors of apoptosis proteins are implicated in promoting cancer cells survival and resistance toward immune surveillance and chemotherapy. Second mitochondria-derived activator of caspases (SMAC) mimetics are novel compounds developed to mimic the inhibitory effect of the endogenous SMAC/DIABLO on these IAPs. Here, we examined the potential effects of the novel SMAC mimetic BV6 on different human cancer cell lines. Our results indicated that BV6 was able to induce cell death in different human cancer cell lines. Mechanistically, BV6 dose dependently induced degradation of IAPs, including cIAP1 and cIAP2. This was coincided with activating the non-canonical NF -kappa B (NF-κB) pathway, as indicated by stabilizing NF-κB-inducing kinase (NIK) for p100 processing to p52. More interestingly, BV6 was able to sensitize some of the resistant cancer cell lines to apoptosis induced by the death ligands tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) that are produced by different cells of the immune system. Such cell death enhancement was mediated by inducing an additional cleavage of caspase-9 to augment that of caspase-8 induced by death ligands. This eventually led to more processing of the executioner caspase-3 and poly (ADP-ribose) polymerase (PARP). In conclusion, therapeutic targeting of IAPs by BV6 might be an effective approach to enhance cancer regression induced by immune system. Our data also open up the future possibility of using BV6 in combination with other antitumor therapies to overcome cancer drug resistance.

  19. In vivo coordination structural changes of a potent insulin-mimetic agent, bis(picolinato)oxovanadium(IV), studied by electron spin-echo envelope modulation spectroscopy.

    PubMed

    Fukui, K; Fujisawa, Y; OhyaNishiguchi, H; Kamada, H; Sakurai, H

    1999-01-01

    Bis(picolinato)oxovanadium(IV) [VO(pic)2] is one of the most potent insulin-mimetic vanadium complexes. To probe coordination structural changes of this complex in vivo and provide insights into the origin of its high potency, an electron spin-echo envelope modulation (ESEEM) study was performed on organs (kidney, liver and bone) of VO(pic)2- and VOSO4-treated rats. Kidney and liver samples from both types of rats exhibited a 14N ESEEM signal that could be attributed to equatorially coordinating amine nitrogen. The relative intensity of the amine signal was larger for the organs of the rat treated with the less potent VOSO4, suggesting that this amine coordination inhibits the insulin-mimetic activity. The spectra of kidney and liver from the VO(pic)2-treated rat contained a weak signal due to the picolinate imine nitrogen. This suggests that some picolinato species (including both the bispicolinato and a partially decomposed monopicolinato species) still exist in the organs as a minor species, where the proportions of the picolinato species to the total amount of the EPR-detectable VIVO species are estimated as 8-16% in the kidney and 12-24% in the liver. The picolinate ligand presumably serves to prevent VO2+ from being converted into the inactive amine-coordinated species. Bone samples from both types of rats exhibited an ESEEM signal due to 31P nuclei. The VO2+ in bone is therefore most likely incorporated into the hydroxyapatite Ca10(PO4)6(OH)2 matrix, which is consistent with the hypothesis that the bone-accumulated VO2+ is gradually released and transported to other organs as is Ca2+. No 14N signals were observed, even in the bone samples of the VO(pic)2-treated rats, indicating that vanadium uptake by bone requires complete decomposition of the complex.

  20. Real-time examination of aminoglycoside activity towards bacterial mimetic membranes using Quartz Crystal Microbalance with Dissipation monitoring (QCM-D).

    PubMed

    Joshi, Tanmaya; Voo, Zhi Xiang; Graham, Bim; Spiccia, Leone; Martin, Lisandra L

    2015-02-01

    The rapid increase in multi-drug resistant bacteria has resulted in previously discontinued treatments being revisited. Aminoglycosides are effective "old" antibacterial agents that fall within this category. Despite extensive usage and understanding of their intracellular targets, there is limited mechanistic knowledge regarding how aminoglycosides penetrate bacterial membranes. Thus, the activity of two well-known aminoglycosides, kanamycin A and neomycin B, towards a bacterial mimetic membrane (DMPC:DMPG (4:1)) was examined using a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). The macroscopic effect of increasing the aminoglycoside concentration showed that kanamycin A exerts a threshold response, switching from binding to the membrane to disruption of the surface. Neomycin B, however, disrupted the membrane at all concentrations examined. At concentrations above the threshold value observed for kanamycin A, both aminoglycosides revealed similar mechanistic details. That is, they both inserted into the bacterial mimetic lipid bilayer, prior to disruption via loss of materials, presumably aminoglycoside-membrane composites. Depth profile analysis of this membrane interaction was achieved using the overtones of the quartz crystal sensor. The measured data is consistent with a two-stage process in which insertion of the aminoglycoside precedes the 'detergent-like' removal of membranes from the sensor. The results of this study contribute to the insight required for aminoglycosides to be reconsidered as active antimicrobial agents/co-agents by providing details of activity at the bacterial membrane. Kanamycin and neomycin still offer potential as antimicrobial therapeutics for the future and the QCM-D method illustrates great promise for screening new antibacterial or antiviral drug candidates. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. The role of ultraviolet colour in the assessment of mimetic accuracy between Batesian mimics and their models: a case study using ant-mimicking spiders.

    PubMed

    Corcobado, Guadalupe; Herberstein, Marie E; Pekár, Stano

    2016-12-01

    The use of ultraviolet (UV) cues for intra- and inter-specific communication is common in many animal species. Still, the role of UV signals under some predator-prey contexts, such as Batesian mimicry, is not clear. Batesian mimicry is a defensive strategy by which a palatable species (the mimic) resembles an unpalatable or noxious species (the model) to avoid predation. This strategy has evolved independently in many different taxa that are predated by species capable of UV perception. Moreover, there is considerable variation in how accurately Batesian mimics resemble their models across species. Our aim was to investigate how UV colour contributed to mimetic accuracy using several ant-mimicking spider species as a case study. We measured the reflectance spectrum (300-700 nm) for several species of mimics and models, and we tested whether they differ in visible and UV colour. We modelled whether two different predators could discriminate between mimics and models using colour information. We found that generally, ant-mimicking spiders differed significantly from their ant models in UV colour and that information from the visible range of light cannot be extrapolated into the UV. Our modelling suggested that wasps should be able to discriminate between mimics and models combining information from visible and the UV light, whereas birds may not discriminate between them. Thus, we show that UV colour can influence mimic accuracy and we discuss its potential role in Batesian mimicry. We conclude that colour, especially in the UV range, should be taken into account when measuring mimetic accuracy.

  2. The role of ultraviolet colour in the assessment of mimetic accuracy between Batesian mimics and their models: a case study using ant-mimicking spiders

    NASA Astrophysics Data System (ADS)

    Corcobado, Guadalupe; Herberstein, Marie E.; Pekár, Stano

    2016-12-01

    The use of ultraviolet (UV) cues for intra- and inter-specific communication is common in many animal species. Still, the role of UV signals under some predator-prey contexts, such as Batesian mimicry, is not clear. Batesian mimicry is a defensive strategy by which a palatable species (the mimic) resembles an unpalatable or noxious species (the model) to avoid predation. This strategy has evolved independently in many different taxa that are predated by species capable of UV perception. Moreover, there is considerable variation in how accurately Batesian mimics resemble their models across species. Our aim was to investigate how UV colour contributed to mimetic accuracy using several ant-mimicking spider species as a case study. We measured the reflectance spectrum (300-700 nm) for several species of mimics and models, and we tested whether they differ in visible and UV colour. We modelled whether two different predators could discriminate between mimics and models using colour information. We found that generally, ant-mimicking spiders differed significantly from their ant models in UV colour and that information from the visible range of light cannot be extrapolated into the UV. Our modelling suggested that wasps should be able to discriminate between mimics and models combining information from visible and the UV light, whereas birds may not discriminate between them. Thus, we show that UV colour can influence mimic accuracy and we discuss its potential role in Batesian mimicry. We conclude that colour, especially in the UV range, should be taken into account when measuring mimetic accuracy.

  3. Urchin-like (gold core)@(platinum shell) nanohybrids: A highly efficient peroxidase-mimetic system for in situ amplified colorimetric immunoassay.

    PubMed

    Gao, Zhuangqiang; Xu, Mingdi; Lu, Minghua; Chen, Guonan; Tang, Dianping

    2015-08-15

    The development of signal-amplified colorimetric immunoassay relies on the design of highly efficient signal-transduction tags. One promising route is to exploit a novel enzyme mimetic system as the signal label. Herein, we report that urchin-like (gold core)@(platinum shell) nanohybrids (Au@PtNHs) can be utilized as a highly efficient peroxidase mimetic system for in situ amplified colorimetric immunoassay of prostate-specific antigen (PSA, one kind of tumor marker). Initially, urchin-like Au@PtNHs were discovered to outperform horseradish peroxidase (HRP) by a vast margin in terms of the turnover number toward hydrogen peroxide (H2O2)-3,3',5,5'-tetramethylbenzidine (TMB) system and the stability against high temperatures and HRP inhibitors. Based on this discovery, the assay was simply carried out on a capture antibody-immobilized microplate by using the Au@PtNH-labeled detection antibody as a signal-transduction tag with a sandwich-type assay mode. The colorimetric signal stemmed from the labeled Au@PtNHs toward catalytic oxidation of TMB-H2O2 system. Experimental results indicated that the Au@PtNH-based colorimetric immunoassay could display a good colorimetric response toward PSA in the dynamic working range of 5-500 pg mL(-1) with a low detection limit of 2.9 pg mL(-1). Meanwhile, the developed immunoassay exhibited good precision and reproducibility, high specificity and acceptable accuracy for the detection of clinical serum samples. These results open up a new horizon for the development of highly sensitive, highly stable and inexpensive non-enzyme immunoassay platforms as an alternative to conventional enzyme-based immunoassay platforms. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Absorption, transport and insulin-mimetic properties of bis(maltolato)oxovanadium (IV) in streptozotocin-induced hyperglycemic rats by integrated mass spectrometric techniques.

    PubMed

    Iglesias-González, T; Sánchez-González, C; Montes-Bayón, M; Llopis-González, J; Sanz-Medel, A

    2012-01-01

    The use of V(IV) complexes as insulin-enhancing agents has been increasing during the last decade. Among them, 3-hydroxy-2-methyl-4-pyrone and 2-ethyl-3-hydroxy-4-pyrone (maltol and ethyl maltol, respectively) have proven to be especially suitable as ligands for vanadyl ions. In fact, they have passed phase I and phase II clinical trials, respectively. However, the mechanism through which those drugs exert their insulin-mimetic properties is still not fully understood. Thus, the aim of this study is to obtain an integrated picture of the absorption, biodistribution and insulin-mimetic properties of the bis(maltolato)oxovanadium (IV) (BMOV) in streptozotocin-induced hyperglycaemic rats. For this purpose, BMOV hypoglycaemic properties were evaluated by monitoring both the circulating glucose and the glycohemoglobin, biomarkers of diabetes mellitus. In both cases, the results were drug concentration dependent. Using doses of vanadium at 3 mg/day, it was possible to reduce the glycaemia of the diabetic rats to almost control levels. BMOV absorption experiments have been conducted by intestinal perfusion revealing that approximately 35% of V is absorbed by the intestinal cells. Additionally, the transport of the absorbed vanadium (IV) by serum proteins was studied. For this purpose, a speciation strategy using high-performance liquid chromatography (HPLC) for separation and inductively coupled serum mass spectrometry, ICP-MS, for detection has been employed. The obtained HPLC-ICP-MS results, confirmed by MALDI-MS data, showed evidence that V, administered orally, is uniquely bound to transferrin in rat serum.

  5. Fabrication highly dispersed Fe3O4 nanoparticles on carbon nanotubes and its application as a mimetic enzyme to degrade Orange II.

    PubMed

    Deng, Jingheng; Wen, Xianghua; Li, Jiaxi

    2016-09-01

    Fe3O4 nanoparticles were grown in situ on carbon nanotubes (CNTs) by a solvothermal method. The Fe3O4/CNTs composites were characterised by the Brunauer-Emmett-Teller method and transmission electron microscopy. The results indicated that the Fe3O4 nanoparticles were uniformly deposited on CNTs, and the average diameter was approximately 7.0 nm. The Fe3O4/CNTs were applied as an enzyme mimetic to decompose Orange II, and the decomposing conditions were optimised. At 500 mg L(-1) of Fe3O4/CNTs in the presence of 15.0 mmol L(-1) of H2O2, at 30°C, it degraded 94.0% of Orange II (0.25 mmol L(-1), pH = 3.5), showing higher catalytic activity than pure Fe3O4 nanoparticles. The high activity was attributed to the uniform Fe3O4 nanoparticles growing on the side walls of the CNTs and the synergetic effect between Fe3O4 and CNTs. The Fe3O4/CNTs maintained their activity at temperatures as high as 65°C. The Fe3O4/CNTs presented high reusability and stability even after eight uses. These data proved that the Fe3O4/CNTs-catalysed degradation is a promising technique for wastewater treatment. Fe3O4 nanoparticles were grown in situ on carbon nanotubes (CNTs) by a solvothermal method. The Fe3O4/CNTs was applied as a mimetic enzyme to decompose Orange II. The Fe3O4/CNTs were collected after the reaction by applying an external magnetic field and can use repeatedly.

  6. Thromboxane and isoprostanes as inflammatory and vasoactive mediators in black walnut heartwood extract induced equine laminitis.

    PubMed

    Noschka, Erik; Moore, James N; Peroni, John F; Lewis, Stephen J; Morrow, Jason D; Robertson, Tom P

    2009-06-15

    Inflammation and vascular dysfunction occur concurrently during the prodromal stages of equine laminitis. The aim of this study was to provide insights into the role that thromboxane and isoprostanes may play in the development of black walnut heartwood extract (BWHE)-induced laminitis. Horses were divided into two groups, either control or BWHE-administered horses. Plasma concentrations of thromboxane increased transiently after administration of BWHE and coincided with the nadir in white blood cell counts, whereas plasma concentrations of iso-prostaglandin PGF(2alpha) (iso-PGF(2alpha)) did not change in either group. At 12h (for the control group) or Obel grade 1 laminitis (for the BWHE group) the horses were euthanized and laminar tissue collected. Laminar arteries and veins were used in functional studies with vasoconstrictor substances and tissue samples were used for the determination of laminar iso-PGF(2alpha) concentrations. Laminar tissue concentrations of iso-PGF(2alpha) were significantly greater in BWHE horses when compared to control horses. In parallel studies concentrations of iso-PGF(2alpha) in laminar tissue samples obtained 1.5 and 3h after administration of BWHE were indistinguishable from those for control horses at 3 or 12h after administration of an equal volume of water. Laminar vessel constrictor responses to either a thromboxane mimetic (U46619), iso-prostaglandin PGE(2) (iso-PGE(2)) or iso-PGF(2alpha) were determined using small vessel myographs. In some vessels, the effects of putative prostanoid and thromboxane receptor antagonists, SQ 29,548, SC-19220 and AH 6809, upon contractile responses were determined. In control horses, U46619, iso-PGF(2alpha) and iso-PGE(2) more potently and efficaciously constricted laminar veins when compared to laminar arteries. Responses of laminar veins from BWHE horses to iso-PGE(2) were similar to those of laminar veins from control horses, whereas iso-PGF(2alpha) elicited significantly greater responses

  7. UDP-sugars activate P2Y14 receptors to mediate vasoconstriction of the porcine coronary artery.

    PubMed

    Abbas, Zainab S B; Latif, M Liaque; Dovlatova, Natalia; Fox, Sue C; Heptinstall, Stan; Dunn, William R; Ralevic, Vera

    2017-12-15

    UDP-sugars can act as extracellular signalling molecules, but relatively little is known about their cardiovascular actions. The P2Y 14 receptor is a G i/o -coupled receptor which is activated by UDP-glucose and related sugar nucleotides. In this study we sought to investigate whether P2Y 14 receptors are functionally expressed in the porcine coronary artery using a selective P2Y 14 receptor agonist, MRS2690, and a novel selective P2Y 14 receptor antagonist, PPTN (4,7-disubstituted naphthoic acid derivative). Isometric tension recordings were used to evaluate the effects of UDP-sugars in porcine isolated coronary artery segments. The effects of the P2 receptor antagonists suramin and PPADS, the P2Y 14 receptor antagonist PPTN, and the P2Y 6 receptor antagonist MRS2578, were investigated. Measurement of vasodilator-stimulated phosphoprotein (VASP) phosphorylation using flow cytometry was used to assess changes in cAMP levels. UDP-glucose, UDP-glucuronic acid UDP-N-acetylglucosamine (P2Y 14 receptor agonists), elicited concentration-dependent contractions of the porcine coronary artery. MRS2690 was a more potent vasoconstrictor than the UDP-sugars. Concentration dependent contractile responses to MRS2690 and UDP-sugars were enhanced in the presence of forskolin (activator of cAMP), where the level of basal tone was maintained by addition of U46619, a thromboxane A 2 mimetic. Contractile responses to MRS2690 were blocked by PPTN, but not by MRS2578. Contractile responses to UDP-glucose were also attenuated by PPTN and suramin, but not by MRS2578. Forskolin-induced VASP-phosphorylation was reduced in porcine coronary arteries exposed to UDP-glucose and MRS2690, consistent with P2Y 14 receptor coupling to G i/o proteins and inhibition of adenylyl cyclase activity. Our data support a role of UDP-sugars as extracellular signalling molecules and show for the first time that they mediate contraction of porcine coronary arteries via P2Y 14 receptors. Copyright © 2018 The

  8. Apolipoprotein A-I mimetic peptides inhibit expression and activity of hypoxia-inducible factor-1α in human ovarian cancer cell lines and a mouse ovarian cancer model.

    PubMed

    Gao, Feng; Chattopadhyay, Arnab; Navab, Mohamad; Grijalva, Victor; Su, Feng; Fogelman, Alan M; Reddy, Srinivasa T; Farias-Eisner, Robin

    2012-08-01

    Our previous results demonstrated that the apolipoprotein A-I (apoA-I) mimetic peptides L-4F and L-5F inhibit vascular endothelial growth factor production and tumor angiogenesis. The present study was designed to test whether apoA-I mimetic peptides inhibit the expression and activity of hypoxia-inducible factor-1α (HIF-1α), which plays a critical role in the production of angiogenic factors and angiogenesis. Immunohistochemistry staining was used to examine the expression of HIF-1α in tumor tissues. Immunoblotting, real-time polymerase chain reaction, immunofluorescence, and luciferase activity assays were used to determine the expression and activity of HIF-1α in human ovarian cancer cell lines. Immunohistochemistry staining demonstrated that L-4F treatment dramatically decreased HIF-1α expression in mouse ovarian tumor tissues. L-4F inhibited the expression and activity of HIF-1α induced by low oxygen concentration, cobalt chloride (CoCl(2), a hypoxia-mimic compound), lysophosphatidic acid, and insulin in two human ovarian cancer cell lines, OV2008 and CAOV-3. L-4F had no effect on the insulin-induced phosphorylation of Akt, but inhibited the activation of extracellular signal-regulated kinase and p70s6 kinase, leading to the inhibition of HIF-1α synthesis. Pretreatment with L-4F dramatically accelerated the proteasome-dependent protein degradation of HIF-1α in both insulin- and CoCl(2)-treated cells. The inhibitory effect of L-4F on HIF-1α expression is in part mediated by the reactive oxygen species-scavenging effect of L-4F. ApoA-I mimetic peptides inhibit the expression and activity of HIF-1α in both in vivo and in vitro models, suggesting the inhibition of HIF-1α may be a critical mechanism responsible for the suppression of tumor progression by apoA-I mimetic peptides.

  9. EphA2/Ephrin-A1 Signaling Complexes Restrict Corneal Epithelial Cell Migration

    PubMed Central

    Kaplan, Nihal; Fatima, Anees; Peng, Han; Bryar, Paul J.; Lavker, Robert M.; Getsios, Spiro

    2012-01-01

    Purpose. Eph/ephrin signaling proteins are present in the corneal epithelium, where their function remains unknown. The authors examined the role of the EphA2 receptor and ephrin-A1 ligand in human corneal epithelial cell migration. Methods. Immunohistochemical analysis of EphA2 and ephrin-A1 in healthy and diabetic corneas was performed in concert with linear scratch wound healing studies in primary and telomerase-immortalized human corneal epithelial cells. Corneal epithelial cells were exposed to a soluble ephrin-A1-Fc peptide mimetic that targets EphA2 to trigger receptor phosphorylation and subsequent downregulation. Genetic modulation of EphA2 and ephrin-A1 levels was combined with manipulation of Erk1/2 or Akt signaling during wound healing. Results. EphA2 was immunolocalized to human corneal epithelial cells in vivo and in vitro. Ephrin-A1 ligand targeting of EphA2 restricted the ability of corneal epithelial cells to seal linear scratch wounds in a manner that was associated with a transient reduction in Erk1/2 and Akt activation state. Ephrin-A1-Fc treatment delayed wound healing independently of Mek-Erk1/2 signaling but was no longer capable of restricting migration after pharmacologic blockade of the PI3K-Akt pathway. Interestingly, ephrin-A1 immunoreactivity was increased in the corneal epithelia of diabetic individuals, mice maintained on a high-fat diet, or cultured corneal epithelial cells exposed to high glucose, which exhibit impaired Akt signaling and slower wound healing responses. Conclusions. EphA2 attenuates corneal epithelial cell migration when stimulated by ephrin-A1 ligand in a manner that involves the suppression of Akt. Elevated levels of ephrin-A1 may contribute to diabetic keratopathies by persistently engaging EphA2 and prohibiting Akt-dependent corneal epithelial repair processes. PMID:22247486

  10. A new insulin-mimetic vanadyl complex, (N-pyridylmethylaspartate)oxovanadium(IV) with VO(N2O2) coordination mode, and evaluation of its effect on uptake of D-glucose by Ehrlich ascites tumour cells.

    PubMed

    Tawa, R; Uchida, K; Taniyama, J; Fujisawa, Y; Fujimoto, S; Nagaoka, T; Kanamori, K; Sakurai, H

    1999-02-01

    Because it has been confirmed that the vanadyl(IV) ion and its complexes act as insulin mimetics, a new organic vanadyl complex, (N-pyridylmethylaspartate)oxovanadium (VOPASP) with VO(N2O2) coordination mode, was prepared. Development of a simple and rapid in-vitro assay is needed for recognition of potent insulin-mimetic complexes. Treatment of Ehrlich ascites tumour cells with 2-deoxyglucose in the presence of vanadyl sulphate, or other vanadyl complexes with the same coordination mode (VOPASP, bis(picolinate)oxovanadium (VOPA) and bis(6-methyl picolinate)oxovanadium (VOMPA)), in the presence of 2-deoxy-D-[1-3H]glucose ([3H]deoxyglucose), resulted in concentration-dependent uptake of 2-deoxyglucose by the cells. The responses of the cells to the vanadyl complexes were reflected, in part, by results obtained from the free fatty acid-releasing assay using rat adipocytes. These results show that the in-vitro assay with Ehrlich ascites tumour cells provides an accurate and rapid assessment of glucose uptake by the cells. The assay is proposed as a means of predicting the insulin-mimetic activity of the vanadyl complexes and for studying the mechanism of action of the complexes.

  11. Cross-Linking of a CD4-Mimetic Miniprotein with HIV-1 Env gp140 Alters Kinetics and Specificities of Antibody Responses against HIV-1 Env in Macaques.

    PubMed

    Shen, Xiaoying; Bogers, Willy M; Yates, Nicole L; Ferrari, Guido; Dey, Antu K; Williams, William T; Jaeger, Frederick H; Wiehe, Kevin; Sawant, Sheetal; Alam, S Munir; LaBranche, Celia C; Montefiori, David C; Martin, Loic; Srivastava, Indresh; Heeney, Jonathan; Barnett, Susan W; Tomaras, Georgia D

    2017-10-01

    Evaluation of the epitope specificities, locations (systemic or mucosal), and effector functions of antibodies elicited by novel HIV-1 immunogens engineered to improve exposure of specific epitopes is critical for HIV-1 vaccine development. Utilizing an array of humoral assays, we evaluated the magnitudes, epitope specificities, avidities, and functions of systemic and mucosal immune responses elicited by a vaccine regimen containing Env cross-linked to a CD4-mimetic miniprotein (gp140-M64U1) in rhesus macaques. Cross-linking of gp140 Env to M64U1 resulted in earlier increases of both the magnitude and avidity of the IgG binding response than those with Env protein alone. Notably, IgG binding responses at an early time point correlated with antibody-dependent cellular cytotoxicity (ADCC) function at the peak immunity time point, which was higher for the cross-linked Env group than for the Env group. In addition, the cross-linked Env group developed higher IgG responses against a linear epitope in the gp120 C1 region of the HIV-1 envelope glycoprotein. These data demonstrate that structural modification of t