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

A One Pot Synthesis of Novel Bioactive Tri-Substitute-Condensed-Imidazopyridines that Targets Snake Venom Phospholipase A₂

<div><p>Drugs such as necopidem, saripidem, alpidem, zolpidem, and olprinone contain nitrogen-containing bicyclic, condensed-imidazo[1,2-α]pyridines as bioactive scaffolds. In this work, we report a high-yield one pot synthesis of 1-(2-methyl-8-aryl-substitued-imidazo[1,2-α]pyridin-3-yl)ethan-1-onefor the first-time. Subsequently, we performed <i>in silico</i> mode-of-action analysis and predicted that the synthesized imidazopyridines targets Phospholipase A₂ (PLA₂). <i>In vitro</i> analysis confirmed the predicted target PLA₂ for the novel imidazopyridine derivative1-(2-Methyl-8-naphthalen-1-yl-imidazo [1,2-α]pyridine-3-yl)-ethanone (compound <b>3f</b>) showing significant inhibitory activity towards snake venom PLA₂ with an IC₅₀ value of 14.3 μM. Evidently, the molecular docking analysis suggested that imidazopyridine compound was able to bind to the active site of the PLA₂ with strong affinity, whose affinity values are comparable to nimesulide. Furthermore, we estimated the potential for oral bioavailability by Lipinski's Rule of Five. Hence, it is concluded that the compound <b>3f</b> could be a lead molecule against snake venom PLA₂.</p></div

Structure of biologically active imidazo[1, 2-α]pyridines.

<p>Structure of biologically active imidazo[1, 2-α]pyridines.</p

IC₅₀ values of imidazopyridine derivatives on <i>Vipera russelli</i> (RV) venom induced indirect haemolytic activity.

<p>RV venom (1 μg) was pre-incubated with different concentrations of imidazopyridine derivatives for 10 min at 37°C. Assay was performed as described in methods section and IC_<b>50</b> values for individual imidazopyridine derivatives obtained from dose response curve is presented.</p

Correction: Novel Synthetic Oxazines Target NF-kappa B in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo (vol 11, e0163209, 2016)

10.1371/journal.pone.0175659PLOS ONE124e017565

Structure of biologically active imidazo[1, 2-α]pyridines.

<p>Structure of biologically active imidazo[1, 2-α]pyridines.</p

Structure-activity relationships of newly synthesized tri-substituted-condensed-imidazopyridines.

<p>NS: Not Significant</p><p>Structure-activity relationships of newly synthesized tri-substituted-condensed-imidazopyridines.</p

Novel Synthetic Oxazines Target NF-κB in Colon Cancer In Vitro and Inflammatory Bowel Disease In Vivo.

Aberrant activation of nuclear factor kappa B (NF-κB) has been linked with the pathogenesis of several proinflammatory diseases including number of cancers and inflammatory bowel diseases. In the present work, we evaluated the anticancer activity of 1,2-oxazines derivatives against colorectal cancer cell lines and identified 2-((2-acetyl-6,6-dimethyl-4-phenyl-5,6-dihydro-2H-1,2-oxazin-3-yl)methyl)isoindoline-1,3-dione (API) as the lead anticancer agent among the tested compounds. The apoptosis inducing effect of API was demonstrated using flow cytometry analysis and measuring the caspase 3/7 activity in API treated cells. Based on the literature on inhibition of NF-κB by oxazines, we evaluated the effect of 1,2-oxazines against the ability of NF-κB binding to DNA, NF-κB-dependent luciferase expression and IκBα phosphorylation. We found that, API abrogate constitutive activation of NF-κB and inhibits IκBα phosphorylation in HCT116 cells. Our in silico analysis revealed the binding of oxazines to the hydrophobic cavity that present between the interface of p65 and IκBα. Given the relevance with aberrant activation of NF-κB in inflammation bowel disease (IBD), we evaluated the effect of API on dextran sulphate sodium-induced IBD mice model. The treatment of IBD induced mice with API decreased the myeloperoxidase activity in colonic extract, modulated the colon length and serum levels of pro- and anti-inflammatory cytokines such as TNF-α, IFN-γ, IL-6, IL-1β and IL-10. Furthermore, the histological analysis revealed the restoration of the distorted cryptic epithelial structure of colon in the API treated animals. In conclusion, we comprehensively validated the NF-κB inhibitory efficacy of API that targets NF-κB in in vitro colon cancer and an in vivo inflammatory bowel disease model