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1.  Role of NADH: quinone oxidoreductase-1 in the tight junctions of colonic epithelial cells 
BMB Reports  2014;47(9):494-499.
NADH:quinone oxidoreductase 1 (NQO1) is known to be involved in the regulation of energy synthesis and metabolism, and the functional studies of NQO1 have largely focused on metabolic disorders. Here, we show for the first time that compared to NQO1-WT mice, NQO1-KO mice exhibited a marked increase of permeability and spontaneous inflammation in the gut. In the DSS-induced colitis model, NQO1-KO mice showed more severe inflammatory responses than NQO1-WT mice. Interestingly, the transcript levels of claudin and occludin, the major tight junction molecules of gut epithelial cells, were significantly decreased in NQO1-KO mice. The colons of NQO1-KO mice also showed high levels of reactive oxygen species (ROS) and histone deacetylase (HDAC) activity, which are known to affect transcriptional regulation. Taken together, these novel findings indicate that NQO1 contributes to the barrier function of gut epithelial cells by regulating the transcription of tight junction molecules. [BMB Reports 2014;47(9): 494-499]
doi:10.5483/BMBRep.2014.47.9.196
PMCID: PMC4206724  PMID: 24393524
Barrier dysfunction of epithelial cells; Chromosome condensation; Claudin-1; Gut epithelial cell tight junction; Gut inflammation; Histone acetylation/deacetylation; NQO1 knockout mice; Occludin; Transcription
2.  Strapped Calix[4]pyrroles Bearing an 1,3-Indanedione at a β-Pyrrolic Position: Chemodosimeters for the Cyanide Anion 
Organic letters  2009;11(16):3626-3629.
A strapped calix[4]pyrrole bearing an 1,3-indanedione group at a β-pyrrolic position has been synthesized and studied as a ratiometric cyanide selective chemosensor. A concentration-dependent bleaching of the initial yellow color was observed upon addition of the cyanide anion. The bleaching, which was observed exclusively with the cyanide anion, occurred even in the presence of other anions. Spectroscopic studies provides support for a mechanistic interpretation wherein the cyanide anion forms a complex with the receptor (K = 2.78 × 104 M-1) through a fast equilibrium, which is followed by slow nucleophilic addition to the β-position of the 1,3-indanedione group. A minimum inhibitory effect from other anions was observed, a feature that could be beneficial in the selective sensing of the cyanide anion.
doi:10.1021/ol901361h
PMCID: PMC4105216  PMID: 19639968
3.  “Umpolung” Photoinduced Charge Separation in an Anion-bound Supramolecular Complex 
Journal of the American Chemical Society  2008;130(46):15256-15257.
A new supramolecular system, consisting of an expanded porphyrin, cyclo[8]pyrrole (C8) and a pyrene carboxylate (Py) is capable not only of electron transfer upon photoexcitation, but results in “umpolung” or a reversal of the predicted charge-separation behavior in that the higher energy radical ion pair, C8•+–Py•− (2.58 eV) is formed as opposed to C8•−–Py•+ (1.31 eV). This observation is rationalized in terms of the latter radical ion pair, C8•−–Py•+ being in the Marcus inverted region. Transient absorption spectral studies reveal a charge-separated lifetime of 300 µs, which decays to the triplet state of cyclo[8]pyrrole, also an exceedingly long-lived species. The novel features of this non-covalent dyad highlight the potential utility of anion binding in the construction of supramolecular electron transfer systems.
doi:10.1021/ja806813x
PMCID: PMC4105221  PMID: 18950161
4.  The Insect Peptide Coprisin Prevents Clostridium difficile-Mediated Acute Inflammation and Mucosal Damage through Selective Antimicrobial Activity▿ 
Antimicrobial Agents and Chemotherapy  2011;55(10):4850-4857.
Clostridium difficile-associated diarrhea and pseudomembranous colitis are typically treated with vancomycin or metronidazole, but recent increases in relapse incidence and the emergence of drug-resistant strains of C. difficile indicate the need for new antibiotics. We previously isolated coprisin, an antibacterial peptide from Copris tripartitus, a Korean dung beetle, and identified a nine-amino-acid peptide in the α-helical region of it (LLCIALRKK) that had antimicrobial activity (J.-S. Hwang et al., Int. J. Pept., 2009, doi:10.1155/2009/136284). Here, we examined whether treatment with a coprisin analogue (a disulfide dimer of the nine peptides) prevented inflammation and mucosal damage in a mouse model of acute gut inflammation established by administration of antibiotics followed by C. difficile infection. In this model, coprisin treatment significantly ameliorated body weight decreases, improved the survival rate, and decreased mucosal damage and proinflammatory cytokine production. In contrast, the coprisin analogue had no apparent antibiotic activity against commensal bacteria, including Lactobacillus and Bifidobacterium, which are known to inhibit the colonization of C. difficile. The exposure of C. difficile to the coprisin analogue caused a marked increase in nuclear propidium iodide (PI) staining, indicating membrane damage; the staining levels were similar to those seen with bacteria treated with a positive control for membrane disruption (EDTA). In contrast, coprisin analogue treatment did not trigger increases in the nuclear PI staining of Bifidobacterium thermophilum. This observation suggests that the antibiotic activity of the coprisin analogue may occur through specific membrane disruption of C. difficile. Thus, these results indicate that the coprisin analogue may prove useful as a therapeutic agent for C. difficile infection-associated inflammatory diarrhea and pseudomembranous colitis.
doi:10.1128/AAC.00177-11
PMCID: PMC3186999  PMID: 21807975
5.  N-Tosylpyrrolidine Calix[4]pyrrole: Synthesis and Ion Binding Studies 
The Journal of Organic Chemistry  2010;76(4):1005-1012.
The synthesis and preliminary solution phase ion binding properties of the N-tosylpyrrolidine calix[4]pyrrole 2 are reported. This β-octaalkyl substituted calix[4]pyrrole, the first to be prepared via a direct condensation reaction, was obtained by reacting the 3,4-alkyl-functionalized pyrrole 8 with acetone in the presence of an acid catalyst. On the basis of 1H NMR spectroscopic analyses and isothermal titration calorimetry, it was concluded that, compared with the parent, β-unsubstituted calix[4]pyrrole (1), compound 2 possesses significantly enhanced binding ability for halide anions in chloroform. Furthermore, 2 proved capable of solubilizing in chloroform solution the otherwise insoluble salts, CsF and CsCl. These effects are ascribed to the interactions between the four tosyl groups present in 2 and the counter cations of the halide anion salts.
doi:10.1021/jo101882r
PMCID: PMC3134555  PMID: 21141913
6.  Anion Responsive TTF-Appended Calix[4]arenes. Synthesis and Study of Two Different Conformers 
The Journal of organic chemistry  2010;76(3):870-874.
Two new cone- and 1,3-alternate-calix[4]arenes (cone-1 and 1,3-alt-1), bearing four modified TTF (tetrathiafulvalene) substituents on the upper rim, have been synthesized. The binding ability of these two sets of conformers for various anions, including F−, Cl−, Br−, I−, PF6−, ClO4−, HSO4−, CH3COO−, H2PO4−, and HP2O73−, was tested in organic media by monitoring the changes in their UV/vis and 1H NMR spectra as a function of added anion, as well as via cyclovoltammetry (CV) (all anions studied as their respective TBA salts). On the basis of the present findings, we propose that incorporation of four TTF units within an overall calix[4]arene-based recognition framework produces a preorganized receptor system that displays a modest preference for the pyrophosphate (HP2O73−) anion.
doi:10.1021/jo1021713
PMCID: PMC3133693  PMID: 21194202
7.  Stopped-Flow Kinetic Analysis of the Interaction of Cyclo[8]pyrrole with Anions 
Journal of the American Chemical Society  2010;132(46):16617-16622.
The on and off rates corresponding to the binding of two test anions (acetate, AcO− and dihydrogen phosphate, H2PO4− studied as their tetrabutylammonium salts) to diprotonated cyclo[8]pyrrole have been determined in CH3CN using stopped-flow analyses carried out at various temperatures. For dihydrogen phosphate, this afforded the activation enthalpies and entropies associated with both off and on processes. The different dynamic behavior seen for these test anions underscores the utility of kinetic analyses as a possible new tool for the advanced characterization of anion receptors.
doi:10.1021/ja107471x
PMCID: PMC3078044  PMID: 21043496
Anion Binding; Kinetics; Stopped-Flow
8.  Ion pair receptors† 
Chemical Society reviews  2010;39(10):3784-3809.
Compared with simple ion receptors, which are able to bind either a cation or an anion, ion pair receptors bearing both a cation and an anion recognition site offer the promise of binding ion pairs or pairs of ions strongly as the result of direct or indirect cooperative interactions between co-bound ions. This critical review focuses on the recent progress in the design of ion pair receptors and summarizes the various binding modes that have been used to accommodate ion pairs (110 references).
doi:10.1039/c002694h
PMCID: PMC3016456  PMID: 20737073
9.  Phosphatidylinositol phosphates directly bind to neurofilament light chain (NF-L) for the regulation of NF-L self assembly 
Experimental & Molecular Medicine  2011;43(3):153-160.
Phosphatidylinositol phosphates (PtdInsPs) are ubiquitous membrane phospholipids that play diverse roles in cell growth and differentiation. To clarify the regulation mechanism acting on neurofilament light chain (NF-L) self assembly, we examined the effects of various PtdInsPs on this process. We found that PtdInsPs, including PI(4,5)P2, directly bind to the positively charged Arg54 of murine NF-L, and this binding promotes NF-L self assembly in vitro. Mutant NF-L (R53A/R54A) proteins lacking binding affinity to PtdInsPs did not have the same effect, but the mutant NF-L proteins showed greater self assembly than the wild-type in the absence of any PtdInsP. These results collectively suggest that Arg54 plays a pivotal role in NF-L self assembly by binding with PtdInsPs.
doi:10.3858/emm.2011.43.3.019
PMCID: PMC3068298  PMID: 21339697
neurofilament protein L; phosphatidylinositol phosphates; phospholipase Cγ
11.  A double point mutation in PCL-γ1 (Y509A/F510A) enhances Y783 phosphorylation and inositol phospholipid-hydrolyzing activity upon EGF stimulation 
Experimental & Molecular Medicine  2010;42(3):216-222.
Growth factor stimulation induces Y783 phosphorylation of phosphoinositide-specific PLC-γ1, and the subsequent activation of this enzyme in a cellular signaling cascade. Previously, we showed that a double point mutation, Y509A/F510A, of PLC-γ1, abolished interactions with translational elongation factor 1-α. Here, we report that the Y509A/F510A mutant PLC-γ1 displayed extremely high levels of Y783 phosphorylation and enhanced catalytic activity, compared to wild-type PLC-γ1, upon treatment of COS7 cells with EGF. In quiescent COS7 cells, the Y509A/F510A mutant PLC-γ1 exhibited a constitutive hydrolytic activity, whereas the wild-type counterpart displayed a basal level of activity. Upon treatment of COS7 cells with EGF, the Y783F mutation in Y509A/F510A PLC-γ1 (Y509A/F510A/Y783F triple mutant) cells also led to an enhanced catalytic activity, whereas Y783F mutation alone displayed a basal level of activity. Our results collectively suggest that the Y509A/F510A mutant is more susceptible to receptor tyrosine kinase-induced Y783 phosphorylation than is wild-type PLC-γ1, but no longer requires Y783 phosphorylation step for the Y509A/F510A mutant PLC-γ1 activation in vivo.
doi:10.3858/emm.2010.42.3.023
PMCID: PMC2845006  PMID: 20164676
phosphatidylinositol 4,5-bisphosphate; phospholipase Cγ; protein-tyrosine kinases; src homology domains
12.  Crown-6-Calix[4]arene Capped Calix[4]pyrrole: An Ion Pair Receptor for Solvent Separated CsF Ions 
Journal of the American Chemical Society  2008;130(39):13162-13166.
An ion pair receptor, 1, containing both cation- and anion-recognizing sites, has been synthesized and characterized. Single crystal X-ray diffraction structural studies and 1H NMR spectroscopic analyses confirm that 1 forms a stable 1:1 complex with CsF in solution and in the solid state in spite of the large separation enforced between the receptor-bound anion and cation. In 9:1 CDCl3/CD3OD, fluoride anion binding within the calix[4]pyrrole core of 1 is not observed in the absence of a co-bound cesium cation; however, it is seen in this solvent mixture under conditions where a Cs+ cation is bound to the crown ether strapped calix[4]arene subunit.
doi:10.1021/ja804976f
PMCID: PMC2645898  PMID: 18774808

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