IDE 1

IDE1 is an inducer of definitive endoderm 1 (IDE1).

In Vitro:IDE1 enhances the definitive endoderm (DE) differentiation of human-induced pluripotent stem cells (hiPSCs) with Activin A/Wnt3a being significantly more potent in both 2D and 3D cultures compared to IDE1. IDE1 could efficiently induces DE differentiation through various protocols in vitro. Treatment of the hiPSCs-derived EBs with IDE-1 shows minor increase (p<0.01) of DE-markers cells compared to Activin A/Wnt3a treatment. IDE1 possess several advantages over other inducing factors including high permeability, influence, diversity, low cost, and easy to use and for the first time, Melton’s team showed that Activin A can be substituted by two cell-permeable small molecules, IDE1 and IDE2. IDE1 could induce phosphorylation of Smad2 after incubation for 24 h or more at levels comparable to those induced by Activin A treatment. Treatment of hiPSCs with IDE1 (2 mM) also leads to endodermal differentiation but with a significantly lower efficiency than Activin A/Wnt3a[1].

References:
[1]. Hoveizi E, et al. Definitive endoderm differentiation of human-induced pluripotent stem cells using signaling molecules and IDE1 in three-dimensional polymer scaffold. J Biomed Mater Res A. 2014 Nov;102(11):4027-36.

2-(Pyridinium-1-yl)-1,1-bis(perfluoroalkylsulfonyl)ethan-1-ide: A Practical Reagent for Synthesis of Strongly Acidic 1,1-Bis(perfluoroalkylsulfonyl)alkanes.[Pubmed:28266793]

Chemistry. 2017 Jun 16;23(34):8203-8211.

On mixing (Rf SO2 )2 CH2 (Rf =perfluoroalkyl), paraformaldehyde, and substituted pyridines, a three-component reaction proceeded smoothly to give unusual zwitterions bearing both pyridinium and stabilized carbanion moieties in good to excellent yields. Of these, 2-fluoropyridinium derivatives rapidly dissociated in acetonitrile to give equilibrium mixtures of the zwitterions and (Rf SO2 )2 C=CH2 /2-fluoropyridine, as confirmed by detailed variable-temperature NMR studies. The dynamic behavior of such 2-fluoropyridinium compounds allows them to be used as shelf-stable, easy-to-handle sources of (Rf SO2 )2 C=CH2 . With these reagents, strongly acidic carbon acids (Rf SO2 )2 CHR were synthesized, which served as a new type of acid catalysts. Moreover, C-C bond-forming reactions with a ketene silyl acetal proceeded efficiently with Tf2 C=CH2 generated in situ.

Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART (cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, randomized, multicentre trial (IMEA 040 DATA trial).[Pubmed:27068399]

J Antimicrob Chemother. 2016 Aug;71(8):2252-61.

OBJECTIVES: Boosted PIs are commonly prescribed in patients presenting with advanced HIV infection. We assessed the efficacy and tolerability of once-daily ritonavir-boosted atazanavir or darunavir plus two NRTIs in HIV-1-infected ART-naive patients with severe immunosuppression, targeting at least an 85% success rate at week 48. METHODS: This 48 week, open-label, non-comparative, randomized, multicentre trial included ART-naive patients with CD4 cell counts <200 cells/mm(3), with plasma HIV-1 RNA >1000 copies/mL and without genotypic mutations conferring resistance to the study drugs. Patients were randomized (1:1) to receive once-daily atazanavir/ritonavir (300/100 mg) or darunavir/ritonavir (800/100 mg) plus tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine. The primary endpoint was treatment success, defined as plasma HIV-1 RNA

Identification and functional characterization of a putative IDE, C28F5.4 (ceIDE-1), in Caenorhabditis elegans: Implications for Alzheimer's disease.[Pubmed:27443962]

Biochim Biophys Acta. 2016 Nov;1860(11 Pt A):2454-2462.

Insulin-degrading enzyme (IDE) is a zinc metalloprotease, known to degrade insulin peptide and amyloid-beta (Abeta); the key protein involved in Alzheimer's disease (AD). Considering the important role played by IDE in disease progression of AD and type 2 diabetes mellitus (T2DM), we endeavored to identify the Caenorhabditis elegans (C. elegans) IDE orthologous genes and test them for their role in AD related outcomes. We employed bioinformatics, reverse genetics and molecular biology approaches towards identification and functional characterization of putative IDE candidates in C. elegans. Using in-silico analysis we have identified seven C. elegans genes that possess HXXEH motif, an identifying marker of IDE. We further carried out functional analysis of the identified genes in Abeta expressing C. elegans strain CL4176 [myo-3/Abeta1-42 long 3'-UTR] via studying effect on Abeta induced toxicity, cholinergic neuroanatomy, content of acetylcholine/acetylcholine-esterase, extent of reactive oxygen species and expression of FOXO transcription factor DAF-16. Our findings reveal that amongst the identified putative IDE orthologs, a functionally uncharacterized gene C28F5.4 had a profound effect on the tested endpoints. Knocking down C28F5.4 modulated the AD associated conditions by decreasing Abeta induced toxicity, severely compromising cholinergic neuroanatomy, reducing expression of acetylcholine-transporter, decreasing acetylcholine content, elevating ROS, with no effect on DAF-16 stress-response protein. These studies provide crucial insight into the structural/functional orthology of IDEs across human and nematode species and further our understanding of the involvement of these proteins and insulin pathway in AD. Further studies could aid in identifying novel drug-targets and in understanding the common modulating factors between AD and T2DM.

Small molecules efficiently direct endodermal differentiation of mouse and human embryonic stem cells.[Pubmed:19341624]

Cell Stem Cell. 2009 Apr 3;4(4):348-58.

An essential step for therapeutic and research applications of stem cells is the ability to differentiate them into specific cell types. Endodermal cell derivatives, including lung, liver, and pancreas, are of interest for regenerative medicine, but efforts to produce these cells have been met with only modest success. In a screen of 4000 compounds, two cell-permeable small molecules were indentified that direct differentiation of ESCs into the endodermal lineage. These compounds induce nearly 80% of ESCs to form definitive endoderm, a higher efficiency than that achieved by Activin A or Nodal, commonly used protein inducers of endoderm. The chemically induced endoderm expresses multiple endodermal markers, can participate in normal development when injected into developing embryos, and can form pancreatic progenitors. The application of small molecules to differentiate mouse and human ESCs into endoderm represents a step toward achieving a reproducible and efficient production of desired ESC derivatives.

Using small molecules to great effect in stem cell differentiation.[Pubmed:19427285]

Cell Stem Cell. 2009 May 8;4(5):373-4.

Several recent reports, including two Cell Stem Cell papers (Zhu et al., 2009 [this issue]; Borowiak et al., 2009), screened small molecule libraries for compounds that promote embryonic stem cell differentiation. Their combined success helps bypass challenges associated with using natural protein factors and has revealed insights into controlling stem cell differentiation.