Resultative Compound Verb in Modern Chinese : A Comment on Imai(1985) and Lu(1986)

<p>A. API and DMO suppresses NF-κB DNA binding ability in HCT116 cells. HCT116 cells were treated with DMO and API at indicated doses, nuclear extracts were prepared, and 20 μg of the nuclear extract protein was used for the ELISA-based DNA-binding assay *p<0.05; **p<0.005). B & C. NF-κB responsive elements linked to a luciferase reporter gene were transfected with wild-type or dominant-negative IκB and transfected cancer cells were treated at indicated doses for 6 h and luciferase activity was measured as described in Materials and Methods section. All luciferase experiments were done in triplicate and repeated twice (*p<0.05; **p<0.005). D. API abrogates constitutive IκBα phosphorylation in dose-dependent manner in HCT116 cells. HCT116 cells were treated with different concentrations of API (0, 5, 10 and 20 μM) for 6 h and cytoplasmic extract was prepared. Lysates were resolved on SDS gel and electrotransferred to a nitrocellulose membrane and probed with anti-phospho-IκBα/IκBα. The blot was washed, exposed to HRP-conjugated secondary antibodies for 1 h, and finally examined by chemiluminescence. GAPDH was used as loading control.</p

Stimuli-Responsive and Hemocompatible Pseudozwitterionic Interfaces

We report a novel biomacromolecular formula for the design of hemocompatible gel interfaces of <i>N</i>-isopropylacrylamide (NIPAAm) and mixed-charge pairs of [2-(methacryloyloxy)­ethyl]­trimethyl­ammonium (TMA) and 3-sulfopropyl methacrylate (SA) with overall electrical neutrality. The study stresses on how well-defined compositions of nonionic NIPAAm and pseudozwitterionic TMA/SA in the poly­(NIPAAm-<i>co</i>-TMA/SA) hydrogels along with environmental conditions (temperature, ionic strength, and solution pH) affect swelling and adhesion of biofoulants on their surfaces. When challenged with plasma proteins, bacteria, recalcified platelets, or whole blood, stimuli-responsive hydrogels better resisted their adhesion as the content of mixed charges in the copolymer increased, to reach nonbiofouling for the gels made of 100% TMA/SA. The low hemolytic activity (0.5%) associated with a long plasma clotting time (10 min) suggests excellent hemocompatibility excellent hemocompatibility. Finally, hydrogels containing both NIPAAm and TMA/SA tend to exhibit preferential adhesion of leukocytes

Zwitterionic Modifications for Enhancing the Antifouling Properties of Poly(vinylidene fluoride) Membranes

The development of effective antibiofouling membranes is critical for many scientific interests and industrial applications. However, the existing available membranes often suffer from the lack of efficient, stable, and scalable antifouling modification strategy. Herein, we designed, synthesized, and characterized alternate copolymers of p­(MAO–DMEA) (obtained by reaction between poly­(maleic anhydride-<i>alt</i>-1-octadecene) and <i>N</i>,<i>N</i>-dimethylene­diamine) and p­(MAO–DMPA) (obtained by reaction between poly­(maleic anhydride-<i>alt</i>-1-octadecene) and 3-(dimethyl­amino)-1-propyl­amine) of different carbon space length (CSL) using a ring-opening zwitterionization. We coated these copolymers on poly­(vinylidene fluoride) (PVDF) membranes using a self-assembled anchoring method. Two important design parametersthe CSL of polymers and the coating density of polymers on membranewere extensively examined for their effects on the antifouling performance of the modified membranes using a series of protein, cell, and bacterial assays. Both zwitterionic-modified membranes with different coating densities showed improved membrane hydrophilicity, increased resistance to protein, bacteria, blood cells, and platelet adsorption. However, while p­(MAO–DMEA) with two CSLs and p­(MAO–DMPA) with three CSLs only differ by one single carbon between the amino and ammonium groups, such subtle structural difference between the two polymers led to the fact that the membranes self-assembled with MAO–DMEA outperformed those modified with MAO–DMPA in all aspects of surface hydration, protein and bacteria resistance, and blood biocompatibility. This work provides an important structural-based design principle: a subtle change in the CSL of polymers affects the surface and antifouling properties of the membranes. It can help to achieve the design of more effective antifouling membranes for blood contacting applications

Epoxylated Zwitterionic Triblock Copolymers Grafted onto Metallic Surfaces for General Biofouling Mitigation

Titanium and stainless steel materials are widely used in numerous devices or in custom parts for their excellent mechanical properties. However, their lack of biocompatibility seriously limits their usage in the biomedical field. This study focuses on the grafting of triblock copolymers on titanium and stainless steel metal susbtrates for improving their general biofouling resistance. The series of copolymers that we designed is composed of two blocks of zwitterionic sulfobetaine (SBMA) monomers and one block of glycidyl methacrylate (GMA). The number of repeat units forming each block, <i>n</i>, was finely tuned and controlled to 25, 50, 75, or 100, permitting regulation of the grafting thickness, the morphology, and the dependent properties such as the surface hydrophilicity and biofouling resistance. It was shown that the copolymer possessing <i>n</i> = 50 repeat units in each block, corresponding to a molecular weight of about 15.2 kDa, led to the best nonfouling properties, assessed using plasma proteins, blood cells, fibroblasts cells, and various bacteria. This was explained by an optimized grafting degree and chain organization of the copolymer. Lower value (<i>n</i> = 25) and higher values (<i>n</i> = 75, 100) led to low surface coverage and the formation of aggregates, respectively. The best copolymer was grafted onto scalpels (steel) and dental roots (titanium), and antifouling properties demonstrated using Escherichia coli and HT1080 cells. Results of this work show that this unique triblock copolymer holds promise as a potential material for surface modification of biomedical metallic devices, provided a fine-tuning of the blocks organization and length

data_sheet_1.DOCX

<p>Aberrant activation of NF-κB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC), and blockade of NF-κB signaling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-κB activation is of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3-chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (annexin V-propidium iodide-FITC staining), and phosphorylation of NF-κB signaling pathway proteins (IκB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time-dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IκB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-κB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 small interfering RNA blocks CMO-induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65 protein. Thus, we are reporting CMO as an inhibitor of NF-κB signaling pathway.</p

A and B, MDA-MB-231 cells were treated with CIP (25 μM) for indicated time intervals (0, 12, 24, 36 and 48 h) and expression of apoptotic markers (PARP, Procaspase-3), antiapoptotic proteins (Bcl-2, Survivin, VEGF), cell cycle regulator (Cyclin D1) was profiled using western blot analysis.

<p>We observed the significant decline in the expression of PARP, procaspase-3, cyclin D1, VEGF, survivin and Bcl-2 proteins in the time-dependent manner without alteration in the levels of beta actin.</p

Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway

<div><p>Overactivation of PI3K/Akt/mTOR is linked with carcinogenesis and serves a potential molecular therapeutic target in treatment of various cancers. Herein, we report the synthesis of trisubstituted-imidazoles and identified 2-chloro-3-(4, 5-diphenyl-1H-imidazol-2-yl) pyridine (CIP) as lead cytotoxic agent. Naïve Base classifier model of <i>in silico</i> target prediction revealed that CIP targets RAC-beta serine/threonine-protein kinase which comprises the Akt. Furthermore, CIP downregulated the phosphorylation of Akt, PDK and mTOR proteins and decreased expression of cyclin D1, Bcl-2, survivin, VEGF, procaspase-3 and increased cleavage of PARP. In addition, CIP significantly downregulated the CXCL12 induced motility of breast cancer cells and molecular docking calculations revealed that all compounds bind to Akt2 kinase with high docking scores compared to the library of previously reported Akt2 inhibitors. In summary, we report the synthesis and biological evaluation of imidazoles that induce apoptosis in breast cancer cells by negatively regulating PI3K/Akt/mTOR signaling pathway.</p></div

Trisubstituted-Imidazoles Induce Apoptosis in Human Breast Cancer Cells by Targeting the Oncogenic PI3K/Akt/mTOR Signaling Pathway - Fig 1

<p>A, Schematic representation for the synthesis of imidazole based small molecules. B, Breast cancer cells (2.5 X 10⁴/mL, MCF-7 & MDA-MB-231) were plated in triplicate, treated with indicated concentrations (0, 10, 25 and 50 μM) of CIP, and then subjected to MTT assay after 24, 48 and 72 h to analyse proliferation of cells. CIP suppresses the viability of various breast cancer cell lines in a dose- and time-dependent manner.</p

MDA-MB-231 cells were suspended in serum-free DMEM and seeded into the Matrigel transwell chambers and were incubated with CIP (25 μM) for 8 h.

<p>The invading cells were fixed and stained with crystal violet solution and invaded cells were counted in five randomly selected areas. CIP significantly suppressed the cell invasion both in the presence and absence of CXCL12 suggesting that CIP interferes with invasive potential of breast cancer cells.</p

MDA-MB-231 cells were treated with CIP at indicated concentrations (0, 10, 15, 25 and 50 μM) for 8 h and levels of phospho-PDK, phospho-Akt, phospho-mTOR and PDK, Akt, mTOR was analysed using western blotting.

<p>We found that, CIP downregulated the phosphorylation of Akt, PDK and mTOR in a dose-dependent manner without any change in the expression levels of Akt, PDK and mTOR proteins.</p