Bio-inspired first-row transition metal complexes for small molecule activation

Secondary coordination spheres play many important roles in the activity and function of metalloenzymes: they can help stabilize reactive intermediates and shuttle protons or electrons over the course of enzymatic transformations. Accordingly, there have been numerous efforts to mimic these advantageous structural and functional features; indeed, secondary coordination spheres are now employed in a number of synthetic inorganic systems. Our lab has recently designed first-row transition metal complexes bearing secondary coordination spheres. Such complexes have been designed to: 1) be tautomerizable to traverse between hydrogen bond donating and accepting within the secondary coordination 2) facilitate activation of molecules such as O2, NO2- and NO3- 3) catalytically reduce nitrogen-containing oxyanions. In the case of the latter, mechanistic studies have been performed to understand the role of the secondary coordination sphere, revealing its ability to stabilize intermediate as well as shuttle protons/electrons. Early work focused on the synthesis of a tautomerizable ligand platform and its metalation with various first-row transition metal centers. This ligand platform can tautomerize from a pyrrole-2-imine to an azafulvene-amine form, resulting in either hydrogen bond acceptors or hydrogen bond donors in the secondary coordination sphere depending on the binding mode. The synthesis and characterization of a series of Mn(II) complexes with this platform have been described. Of especial importance, intramolecular hydrogen bond interactions between bound substrates and the secondary coordination sphere, as well as independent tautomerization of each arm of the ligand platform, have confirmed that our metal complexes are useful to mimic metalloenzyme. Interested in probing the reactivity of these metal complexes towards biologically relevant molecules, O2, NO2- and NO3- were reacted with metal derivatives of the ligand platform. Upon addition, high-valent Mn(III) and Fe(III) complexes were generated, with noticeable stabilization of the generated species by the secondary coordination sphere. Furthermore, in order to assess the possibility of rendering these reactions catalytic, reduction of the Fe(III) complexes back to the starting Fe(II) complexes was undertaken and accomplished. This result intrigued me and led me to study the catalytic reduction of the nitrogen-containing anions in particular given their significant interest in biological and environmental studies. Mechanistic studies revealed the importance of the secondary coordination sphere in stabilizing intermediates, as well as shuttling protons and electrons throughout the catalytic reaction. Thus, this research demonstrates that metal complexes bearing flexible secondary coordination sphere can model functional and structural features of metalloenzymes, thereby providing important insights into the design of new catalysts to address unmet needs

Anti-inflammatory effect of neo-lignan isoamericanin A via suppression of NF-κB in liposaccharide-stimulated RAW 264.7 cells

Purpose: To investigate the potential anti-inflammatory effects of the seeds of Opuntina humifusa and its active constituents.Methods: The extract of O. humifusa seeds was tested for the inhibition of nitric oxide (NO) production in liposaccharide (LPS)-stimulated RAW 264.7 cells using Griess reagent. The active constituents were isolated using bioassay-guided isolation methods. The effects of the active constituent on NO, proinflammatory cytokines, nuclear factor-kappa B (NF-κB) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (IκB) were evaluated by enzyme-linked immunosorbent assay (ELISA) and western blot analysis.Results: The seed extract of O. humifusa significantly attenuated LPS-induced NO production in RAW 264.7 cells (p < 0.05). Bioassay-guided fractionation resulted in the isolation of isoamericanin A as an active constituent. Isoamericanin A reduced LPS-induced production of NO, iNOS, and proinflammatory cytokines (TNF-α and IL-6) in a concentration-dependent manner (p < 0.05). Furthermore, the effect was accompanied by decreased translocation of NF-κB from the cytosol to the nucleus and the decreased phosphorylation of IκB in the cytosol induced by LPS (p < 0.05).Conclusion: The seed extract of O. humifusa and its active constituent, isoamericanin A, have antiinflammatory effects in LPS-stimulated RAW 264.7 cells, suggesting that they have potentials as antiinflammatory agents. Keywords: Opuntia humifusa seeds, Isoamericanin A, Nitric oxide, RAW 264.7 cells, NF-kappa

Production of Transgenic Cloned Miniature Pigs with Membrane-bound Human Fas Ligand (FasL) by Somatic Cell Nuclear Transfer

Cell-mediated xenograft rejection, including NK cells and CD8+ CTL, is a major obstacle in successful pig-to-human xenotransplantation. Human CD8+ CTL and NK cells display high cytotoxicity for pig cells, mediated at least in part by the Fas/FasL pathway. To prevent cell-mediated xenocytotoxicity, a membrane-bound form of human FasL (mFasL) was generated as an inhibitor for CTL and NK cell cytotoxicity that could not be cleaved by metalloproteinase to produce putative soluble FasL. We produced two healthy transgenic pigs harboring the mFasL gene via somatic cell nuclear transfer (SCNT). In a cytotoxicity assay using transgenic clonal cell lines and transgenic pig ear cells, the rate of CD8+ CTL-mediated cytotoxicity was significantly reduced in transgenic pig's ear cells compared with that in normal minipig fetal fibroblasts. Our data indicate that grafts of transgenic pigs expressing membrane-bound human FasL control the cellular immune response to xenografts, creating a window of opportunity to facilitate xenograft survival

PD-1 deficiency protects experimental colitis via alteration of gut microbiota

Programmed cell death-1 (PD-1) is a coinhibitory molecule and plays a pivotal role in immune regulation. Here, we demonstrate a role for PD-1 in pathogenesis of inflammatory bowel disease (IBD). Wild-type (WT) mice had severe wasting disease during experimentally induced colitis, while mice deficient for PD-1 (PD-1(-/-)) did not develop colon inflammation. Interestingly, PD-1(-/-) mice cohoused with WT mice became susceptible to colitis, suggesting that resistance of PD-1(-/-) mice to colitis is dependent on their gut microbiota. 16S rRNA gene-pyrosequencing analysis showed that PD-1(-/-) mice had altered composition of gut microbiota with significant reduction in Rikenellaceae family. These altered colon bacteria of PD-1(-/-) mice induced less amount of inflammatory mediators from colon epithelial cells, including interleukin (IL)-6, and inflammatory chemokines. Taken together, our study indicates that PD-1 expression is involved in the resistance to experimental colitis through altered bacterial communities of colon.112Ysciescopuskc

Angleâ Insensitive and CMOSâ Compatible Subwavelength Color Printing

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134900/1/adom201600287_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134900/2/adom201600287.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134900/3/adom201600287-sup-0001-S1.pd

Visfatin exerts angiogenic effects on human umbilical vein endothelial cells through the mTOR signaling pathway

AbstractThe biologically active factors known as adipocytokines are secreted primarily by adipose tissues and can act as modulators of angiogenesis. Visfatin, an adipocytokine that has recently been reported to have angiogenic properties, is upregulated in diabetes, cancer, and inflammatory diseases. Because maintenance of an angiogenic balance is critically important in the management of these diseases, understanding the molecular mechanism by which visfatin promotes angiogenesis is very important. In this report, we describe our findings demonstrating that visfatin stimulates the mammalian target of the rapamycin (mTOR) pathway, which plays important roles in angiogenesis. Visfatin induced the expression of hypoxia-inducible factor 1α (HIF1α) and vascular endothelial growth factor (VEGF) in human endothelial cells. Inhibition of the mTOR pathway by rapamycin eliminated the angiogenic and proliferative effects of visfatin. The visfatin-induced increase in VEGF expression was also eliminated by RNA interference-mediated knockdown of the 70-kDa ribosomal protein S6 kinase (p70S6K), a downstream target of mTOR. Visfatin inactivated glycogen synthase kinase 3β (GSK3β) by phosphorylating it at Ser-9, leading to the nuclear translocation of β-catenin. Both rapamycin co-treatment and p70S6K knockdown inhibited visfatin-induced GSK3β phosphorylation at Ser-9 and nuclear translocation of β-catenin. Taken together, these results indicate that mTOR signaling is involved in visfatin-induced angiogenesis, and that this signaling leads to visfatin-induced VEGF expression and nuclear translocation of β-catenin

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A Preliminary Report of Crosslinguistic Evidence on Efficacy of Semantic-Complexity Based Naming Treatment in Korean Aphasics

The current study investigated the efficacy of semantic-complexity based naming treatment in Korean participants with aphasia. Results suggested that both participants showed small to medium effect sizes in the trained items. However, generalization effects were greater in the participant who received treatment on the atypical items first, than the participant who was initiated on the typical items. These results are consistent with the previous findings in English-speaking aphasic participants (Kiran & Thompson, 2003; Kiran, 2008). Preliminary findings of two Korean participants with aphasia added crosslinguistic evidence on efficacy of the semantic complexity based naming treatment