111 research outputs found

    A Small Molecule Inhibitor of Human RAD51 Potentiates Breast Cancer Cell Killing by Therapeutic Agents in Mouse Xenografts

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    <div><p>The homologous recombination pathway is responsible for the repair of DNA double strand breaks. RAD51, a key homologous recombination protein, promotes the search for homology and DNA strand exchange between homologous DNA molecules. RAD51 is overexpressed in a variety of cancer cells. Downregulation of RAD51 by siRNA increases radio- or chemo-sensitivity of cancer cells. We recently developed a specific RAD51 small molecule inhibitor, B02, which inhibits DNA strand exchange activity of RAD51 <i>in</i><i>vitro</i>. In this study, we used human breast cancer cells MDA-MB-231 to investigate the ability of B02 to inhibit RAD51 and to potentiate an anti-cancer effect of chemotherapeutic agents including doxorubicin, etoposide, topotecan, and cisplatin. We found that the combination of B02 with cisplatin has the strongest killing effect on the cancer cells. We then tested the effect of B02 and cisplatin on the MDA-MB-231 cell proliferation in mouse xenografts. Our results showed that B02 significantly enhances the therapeutic effect of cisplatin on tumor cells <i>in</i><i>vivo</i>. Our current data demonstrate that use of RAD51-specific small molecule inhibitor represents a feasible strategy of a combination anti-cancer therapy.</p></div

    The effect of cisplatin and B02 on the time course of tumor growth, A.

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    <p>After 11 days of tumor inoculation, tumors were touchable. Then mice were randomly regrouped (n = 5) and treated on day 11, 13, 15, 17 with either B02 (50 mg/kg), cisplatin (4 mg/kg), or a combination of both. Mice untreated or treated with vehicle (20% DMSO, 20% cremophor, 60% NS) were shown as controls. The tumor volumes were monitored by caliper measurement in each group. The time course of tumor growth presented as a graph. Error bars represent SD. Direct measurement of the weight of tumors tissues dissected from the mice after indicated treatment, B. Mice were sacrificed 43 days after tumor inoculation and the tumors were dissected. The weight of tumors shown in panel B presented as a graph, C. Error bars represent SD.</p

    B02 increases sensitivity of MDA-MB-231 cells to DNA damaging agents.

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    <p>A. The structures of B02, doxorubicin, etoposide, topotecan and cisplatin. B. Survival of MDA-MB-231 cells treated with B02 (○) or with indicated agents in the absence (▴) or presence (▾) of B02 (5 µM). Experiments were repeated at least three times. Error bars represent the standard deviation (SD).</p

    B02 increases sensitivity of 3D-growing MDA-MB-231 cells to cisplatin.

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    <p>A. MDA-MB-231 cells were exposed to cisplatin (in indicated concentrations) in the absence or presence of B02 (5 µM), the colonies were formed in 6-well plates coated with soft agar and stained with 0.005% crystal violet. B. The effect of B02 on survival of MDA-MB-231 cells plotted as a graph. C. The data from panel A plotted as a graph. Error bars represent SD.</p

    Copper-Catalyzed Formal Carbene Migratory Insertion into Internal Olefinic CC Bonds with <i>N</i>‑Tosylhydrazones To Access Iminofuran and 2(3<i>H</i>)‑Furanone Derivatives

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    Efficient copper-catalyzed formal carbene migratory insertion into the olefinic CC bonds of internal olefins, that is, α-oxo ketene <i>N</i>,<i>S</i>-acetals, has been achieved by means of <i>N</i>-tosylhydrazones of ketones as the carbene precursors. Iminofuran derivatives were obtained and further transformed to the corresponding 2­(3<i>H</i>)-furanones and 4-oxobutanoates (γ-ketoesters), respectively, under mild conditions. In a similar fashion, α-thioxo ketene <i>N</i>,<i>S</i>-acetals reacted with <i>N</i>-tosylhydrazones of ketones to afford iminothiophenes. It is suggested that formal carbene migratory insertion into the olefinic CC bond is involved in the overall catalytic cycle, demonstrating a new type of carbene insertion reaction for five-membered heterocycle construction

    Copper-Catalyzed Formal Carbene Migratory Insertion into Internal Olefinic CC Bonds with <i>N</i>‑Tosylhydrazones To Access Iminofuran and 2(3<i>H</i>)‑Furanone Derivatives

    No full text
    Efficient copper-catalyzed formal carbene migratory insertion into the olefinic CC bonds of internal olefins, that is, α-oxo ketene <i>N</i>,<i>S</i>-acetals, has been achieved by means of <i>N</i>-tosylhydrazones of ketones as the carbene precursors. Iminofuran derivatives were obtained and further transformed to the corresponding 2­(3<i>H</i>)-furanones and 4-oxobutanoates (γ-ketoesters), respectively, under mild conditions. In a similar fashion, α-thioxo ketene <i>N</i>,<i>S</i>-acetals reacted with <i>N</i>-tosylhydrazones of ketones to afford iminothiophenes. It is suggested that formal carbene migratory insertion into the olefinic CC bond is involved in the overall catalytic cycle, demonstrating a new type of carbene insertion reaction for five-membered heterocycle construction

    Molecular Insight into 6FD Polyimide-Branched Poly(phenylene) Copolymers: Synthesis, Block Compatibility, and Gas Transport Study

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    A series of 6FDA-DABA (6FD) polyimide and branched poly(phenylene) (PP) block copolymers and homopolymers were successfully synthesized using Diels–Alder and polycondensation reactions. PP and 6FD homopolymer blends in tetrahydrofuran were immiscible. The result coincides with their large chemical dissimilarity and theoretical solubility parameter differences of 25.47 and 33.17 (MJ/m3)1/2. However, 6FD-PP block copolymer solutions were clear, and thin films were robust and creasable. Densities and fractional free volumes (FFV) (0.162–0.346) largely obeyed the rule of mixing, suggesting a “blend-like” morphology. At moderate PP block lengths, two distinct glass transition temperatures (340 and 420 °C) were evident, while large PP block lengths suppressed first-order polyimide transitions entirely. A small-angle X-ray scattering and atomic force microscopy morphological analysis revealed two distinct domains, with separation lengths increasing with the PP block length. Their gas permeation, diffusion, sorption, and separation properties were thoroughly investigated and exhibited a strong correlation with polymer chemistry, block length, and FFV. A block copolymer had an O2 permeability roughly between 6FD and PP, resulting in a 30% increase in O2/N2 selectivity. The N2/CH4 selectivities ranged from 4.2 to 0.58, suggesting that this 6FD-PP system could be efficiently tuned from highly N2-selective to CH4-selective performance. Five structural models, rule-of-mixture, Maxwell, equivalent box model, laminate, and blend, were used to predict gas transport properties. Compared with experimental data, the miscible blend model provided the best results for the 6FD-PP block copolymer system. Block copolymerization by combining highly selective polyimide and highly permeable branched poly(phenylene) provides an opportunity for gas separation tunability and improvement in selected gas pairs

    A Facile Peroxo-Precursor Synthesis Method and Structure Evolution of Large Specific Surface Area Mesoporous BaSnO<sub>3</sub>

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    In this paper, we propose a facile and efficient strategy for synthesizing mesoporous BaSnO<sub>3</sub> with a surface area as large as 67 m<sup>2</sup>/g using a peroxo-precursor decomposition procedure. As far as we know, this is the largest surface area reported in literature for BaSnO<sub>3</sub> materials and may have a potential to greatly promote the technological applications of this kind of functional material in the area of chemical sensors, NO<sub><i>x</i></sub> storage, and dye-sensitized solar cells. The structure evolution of the mesoporous BaSnO<sub>3</sub> from the precursor was followed using a series of techniques. Infrared analysis indicates large amount of protons and peroxo ligands are contained in the peroxo-precursor. Although the crystal structure of the precursor appears cubic according to the analysis of X-ray diffraction data, Raman and Mössbauer spectroscopy results show that the Sn atom is offset from the center of [SnO<sub>6</sub>] octahedron. After calcination at different temperatures, the precursor gradually transforms into BaSnO<sub>3</sub> by release of water and oxygen, and the distortion degree of [SnO<sub>6</sub>] octahedral decreases. However, a number of oxygen vacancies are generated in the calcined samples, which are further confirmed by the physical property measurement system, and they would lower the local symmetry to some content. The concentration of the oxygen vacancies reduces simultaneously as the calcination temperature increases, and their contributions to the total heat capacity of the sample are calculated based on theoretical analysis of heat capacity data in the temperature region below 10 K

    Lychee Pulp-Derived Dietary Fiber-Bound Phenolic Complex Upregulates the SCFAs-GPRs-ENS Pathway and Aquaporins in Loperamide-Induced Constipated Mice by Reshaping Gut Microbiome

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    This study aimed to investigate the effects of the lychee pulp-derived dietary fiber-bound phenolic complex (DF-BPC) on a murine model of loperamide-induced constipation and its molecular mechanism associated with gut microbiota modification. DF-BPC supplementation mitigated loperamide-induced dyschezia, intestinal hypomotility, and colonic impairment, as evidenced by the increased gastro-intestinal transit rate and mucus cell counts. By comparison, short-chain fatty acids (SCFAs) contents and relative abundances of associated genera (Butyricimonas, Clostridium, and Lactobacillus) were effectively upregulated following DF-BPC supplementation. Notably, DF-BPC significantly enhanced expressions of G protein-coupled receptor (GPR) 41 and 43, reaching 1.43- and 1.62-fold increase, respectively. Neurotransmitter secretions were simultaneously altered in DF-BPC-treated mice, suggesting upregulation of the SCFAs-GPRs-enteric nervous system pathway. The overexpression of aquaporins (AQP3, 8, and 9) was stimulated partly through GPRs activation. Mild inflammation associated with constipation was inhibited by suppressing LBP-TLR4-NF-κB signaling translocation. These findings suggest that DF-BPC from lychee pulp has the potential to alleviate constipation in mice through modifying the gut microbiome
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