45 research outputs found

    Enhancing Therapeutic Efficacy of Cisplatin by Blocking DNA Damage Repair

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    Self-repair of nuclear DNA damage is the most known reason that leads to drug resistance of cancer tissue and limited therapeutic efficacy of anticancer drugs. Inhibition of protein phosphatase 2A (PP2A) would block DNA damage-induced defense of cancer cells to suppress DNA repair for enhanced cancer treatment. Here, we combined a PP2A inhibitor LB (4-(3-carboxy-7-oxa-bicyclo[2.2.1]­heptane-2-carbonyl) piperazine-1-carboxylic acid <i>tert</i>-butyl ester) and the DNA damage chemotherapeutic drug cisplatin through a simple physical superposition. The two drugs administrated at a ratio of 1:1 exhibited an optional synergistic antitumor efficacy <i>in vitro</i> and <i>in vivo</i>. LB was demonstrated to specifically activate the protein kinase B (Akt) and mitogen-activated protein kinases (MAPK) signaling pathways by PP2A inhibition to overcome cell cycle arrest caused by cisplatin-induced DNA damage

    Blends of Linear and Long-Chain Branched Poly(l‑lactide)s with High Melt Strength and Fast Crystallization Rate

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    The long-chain branched polylactides (LCB-PLAs) prepared by coupling the hydroxyl-terminated two-arm (linear) and triarm PLA prepolymers of identical arm length with hexamethylenediacianate (HDI) were used to improve the melt rheological and crystallization properties of linear polylactide resin, PLA 4032D from NatureWorks. The blends containing LCB-PLA displayed higher zero shear viscosities, more significant shear shinning, more melt elasticity, and much longer relaxation times together with significant strain hardening in elongational deformation. <i>T</i><sub>g</sub>, <i>T</i><sub>m</sub> and crystallinity (<i>X</i><sub>c</sub>) of linear PLA remained virtually unaffected, but the crystallization rate increased obviously, since the branch points of LCB-PLAs could play a role of nucleating agent. High melt strength, fast crystallization, and favorable miscibility improved the foaming ability of the linear/LCB-PLA blends, substantially

    Rheology and Crystallization of Long-Chain Branched Poly(l‑lactide)s with Controlled Branch Length

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    A series of long-chain branched poly­(l-lactide)­s (LCB-PLAs) with controlled branch length were prepared by a simple and efficient method through a combination of ring-opening polymerization (ROP) of l-lactide and a coupling reaction between the terminal OH groups of the PLA prepolymers and the NCO groups of HDI. The influences of reaction conditions on the synthesis of the LCB-PLAs were investigated, and the structures of the resultant LCB-PLAs were characterized by <sup>1</sup>H NMR spectroscopy and SEC-MALLS. By adjusting the degree of polymerization and the composition of the prepolymers, LCB-PLAs with different branch densities and molecular weights between branch points were obtained. The effect of macromolecular chain branching on the rheology and crystallization of PLA was also investigated. The LCB structure contributed to the enhancement of the zero-shear viscosity, complex viscosity, storage modulus, melt strength, and strain hardening under elongational flow. Thermal behavior indicated that the branch structure resulted in a short nucleation induction period and more rapid crystallization, which can be a guarantee of high-strength foams

    Sequence alignment of the metal binding sites of DR2539 with other DxtR/MntR family members.

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    <p>ScaR (<i>Streptococcus gordonii</i>), SloR (<i>Streptococcus suis</i>), LCAS (<i>Lactobacillus casei</i>), SirR (<i>Corynebacterium glutamicum</i>), TroR (<i>Treponema pallidum</i>), TroR (<i>Treponema denticola</i>), IdeR (<i>Mycobacterium tuberculosis</i>), DtxR (<i>Corynebacterium diptheriae</i>), DR2539 (<i>Deinococcus radiodurans</i>), MntR (<i>Staphylococcus aureus</i>), MntR (<i>Escherichia coli</i>), and MntR (<i>Bacillus subtilis</i>). The sequences were aligned using the CLUSTAL W software. Residues shaded with black represent metal-binding sites that have been studied while residues shaded with grey represent predicted metal binding sites.</p

    Mn(II) and Fe(II) modulate the binding activity of DR2539 <i>in vivo</i>.

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    <p>(A) Effects of divalent metals (50 µM) on expression of pRAZH in <i>D. radiodurans</i>. Data shown are the means ± standard deviations of three independent experiments. (B) Effects of Mn(II) (squares) and Fe(II) (circles) on the expression of pRAZH in wild-type samples expressing DR2539. (C) Effects of Mn(II) (squares) and Fe(II) (circles) on the expression of pRAZH in the <i>dr2539</i> null mutant. (D) Rea-time PCR analysis of the <i>dr1709</i> gene expression using <i>dr0089</i> as internal control gene. Longitudinal axes indicate the change fold of <i>dr1709</i> mRNA relative to controls. Control cells were cultured in medium without Mn(II). *, <i>P</i><0.05 relative to control. The data are the means ± standard deviations of three independent experiments.</p

    His98 plays an important role in DNA binding activity of DR2539.

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    <p>(A) 10 µl cell dilution was dripped on the TGY plate to which 6 mM of Mn(II) had been added. The cells were cultured for 3 days. (B) H98Y mutant and wild-type DR2539 proteins were incubated with p1709b at different concentrations of Mn(II). (C) Quantification of the fluorescence intensity of binding bands was performed using ImageJ. *, <i>P</i><0.05.</p

    DR2539 binds to the MntH promoter DNA fragment in a Mn(II)- and Fe(II)-dependent manner.

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    <p>(A) Schematic of <i>dr1709</i> promoter (p1709a and p1709b) DNA sequence region. The inverted repeat region is shown by the inverted arrows. (B) DR2539 binding to p1709b with increasing quantities of DR2539 and 25 µM Mn(II). (C) and (D) EMSA analysis was performed using DR2539 and p1709b with increasing concentration of Mn(II) or Fe(II). RBS, ribosome binding site; Start, transcription start codon. p1709a and p1709b sequence regions are underlined by straight lines and dashed lines, respectively.</p

    DR0865 binds to the promoter of MntABC in an ion-dependent manner.

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    <p>(A) and (B) DR0865 binding to p2523 and p2284 as the concentration of DR0865 increased. (C) Wild-type R1, <i>dr2539</i> null mutant (<b>Δ</b><i>dr2539</i>), and <i>dr0865</i> null mutant (<b>Δ</b><i>dr0865</i>) were cultured on TGY plates overlaid with filter discs saturated with 1 M solution MnCl<sub>2</sub>. (D) The zone of inhibition was measured from edge of disc after three days. *, <i>P</i><0.05. Data represent the means±deviations of three independent experiments.</p
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