Genes upregulated encoding metabolism enzymes.

<p>Genes upregulated encoding metabolism enzymes.</p

Nitric oxide treatment effects on <i>E. histolytica</i> endoplasmic reticulum with respect to GFP-KDEL-FLAG and calreticulin.

<p>Amoebas were treated with SNP and then fixed and labeled with both anti-FLAG and anti-CRT. Four confocal planes are shown for both untreated (A) and treated (B) samples. GFP-KDEL-FLAG (green), CRT (red), and DAPI (blue). The images show that NO treatment dramatically changes the ER and affects multiple ER markers. The two markers are localized to the same compartment in both treated and untreated samples. Images were analyzed using the iMARIS software to generate 3D models (C). The top panel (C) shows the model of the untreated amoeba from A and the bottom panel depicts the model of the treated amoeba from B. Scale bars equal 30 µm.</p

Immunodetection of PFOR levels upon SNP treatment.

<p>PFOR of 120 kDa was revealed upon SDS-PAGE and immunobloting of crude extracts from SNP-treated and control trophozoites (4, 2 and 1×10⁴ cells). The loaded amount of proteins for each condition is evidenced by actin (43 kDa) immunodetection on the same western blot. Quantification of signal emission did not reveal differences between the tested conditions in 3 independent experiments.</p

Genes modulated by no linked to redox activities.

<p>Genes modulated by no linked to redox activities.</p

Live time-lapse imaging of <i>E. histolytica</i> endoplasmic reticulum during NO treatment.

<p>GFP-KDEL-FLAG transfected amoebas were embedded in a type I collagen matrix treated or not with SNP. One set of images was taken every minutes for an hour. Each stack was acquired using a 0.5 µm Z step. Time points are shown for 0, 25 and 45 min after treatment for both untreated (A) and treated (B) samples. During treatment, the normal organization of the ER begins to change around 25 min after treatment and breaks into vesicles that are found throughout the cytosol by 45 min. Scale bar equals 20 µm.</p

Community-Academic Perspectives in Partnership Development: Lessons from Rural Senegal

This research brief presents quantitative data describing an assessment of a global health partnership focused on cervical cancer prevention in rural Senegal over a two year period (2015-2017)

Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor

SMYD3 has been implicated in a range of cancers; however, until now no potent selective small molecule inhibitors have been available for target validation studies. A novel oxindole series of SMYD3 inhibitors was identified through screening of the Epizyme proprietary histone methyltransferase-biased library. Potency optimization afforded two tool compounds, sulfonamide <b>EPZ031686</b> and sulfamide <b>EPZ030456</b>, with cellular potency at a level sufficient to probe the <i>in vitro</i> biology of SMYD3 inhibition. <b>EPZ031686</b> shows good bioavailability following oral dosing in mice making it a suitable tool for potential <i>in vivo</i> target validation studies

Synthetic Silvestrol Analogues as Potent and Selective Protein Synthesis Inhibitors

Misregulation of protein translation plays a critical role in human cancer pathogenesis at many levels. Silvestrol, a cyclopenta­[<i>b</i>]­benzofuran natural product, blocks translation at the initiation step by interfering with assembly of the eIF4F translation complex. Silvestrol has a complex chemical structure whose functional group requirements have not been systematically investigated. Moreover, silvestrol has limited development potential due to poor druglike properties. Herein, we sought to develop a practical synthesis of key intermediates of silvestrol and explore structure–activity relationships around the C6 position. The ability of silvestrol and analogues to selectively inhibit the translation of proteins with high requirement on the translation–initiation machinery (i.e., complex 5′-untranslated region UTR) relative to simple 5′UTR was determined by a cellular reporter assay. Simplified analogues of silvestrol such as compounds <b>74</b> and <b>76</b> were shown to have similar cytotoxic potency and better ADME characteristics relative to those of silvestrol

Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation - Fig 1

<p><b>Chemical structures of SMYD2 (A) and SMYD3 (B) inhibitors</b>.</p

Anti-proliferative activity of SMYD2 inhibitors.

<p>(A) Correlation plots of (left) cellular methylation IC₅₀ as a function of biochemical IC₅₀ and (right) cell proliferation IC₅₀ as a function of cellular methylation IC₅₀ for SMYD2 inhibitors. (B) Western blot of BTF3 methylation showing dose dependent effects of EPZ032597. Data is representative of two independent experiments. (C) The effect of EPZ032597 on proliferation in a broad panel of cancer cell lines. (D) The effect LLY507 on proliferation of a broad panel of cancer cell lines. Values for C) and D) are the average of three biological replicates; error bars represent standard deviations (not readily visible on scale for all points). The 10 μM value represents the highest dose tested.</p