Biomedical subjects
Theresa Chang
Publications and source records attributed to Theresa Chang.
Increased hexosamine biosynthesis and protein O-GlcNAc levels associated with myocardial protection against calcium paradox and ischemia.
Increased hexosamine biosynthesis pathway (HBP) flux and elevated levels of protein O-linked-N-acetylglucosamine (O-GlcNAc) decrease calcium influx into isolated cardiomyocytes. Increased O-GlcNAc levels also increase tolerance of cells to stress. Therefore, the goal of this study was to test the hypothesis that increasing HBP flux and protein O-GlcNAc levels in the intact heart will increase the tolerance to tissue injury resulting from the calcium paradox and ischemia. We used two strategies that have been shown to increase HBP flux in the intact heart, namely a brief period of streptozotocin-induced diabetes and acute pretreatment of the isolated perfused heart with glucosamine. Isolated perfused rat hearts were exposed to the calcium paradox or to ischemia and reperfusion. Both diabetes and glucosamine significantly improved recovery in the isolated perfused rat heart following the calcium paradox with left ventricular developed pressure (LVDP) returning to ~80% of baseline compared to 0% in controls (P<0.05), and lactate dehydrogenase release being reduced by approximately fivefold (P<0.05). In the diabetic group, azaserine, which inhibits the HBP, restored the sensitivity to the calcium paradox. Glucosamine treatment also improved functional recovery following ischemia/reperfusion (LVDP: 47+/-9% vs. 95+/-4%, P<0.05) and this was associated with a threefold increase in O-GlcNAc levels (P<0.05). Alloxan, an inhibitor of O-GlcNAc-transferase, blocked both the protection seen with glucosamine and the increase in O-GlcNAc. These data demonstrate that activation of the HBP with glucosamine may be a novel strategy for inducing cardioprotection, and that this appears to be mediated by an increase in protein O-GlcNAc levels.
Template-directed synthesis of multiply mechanically interlocked molecules under thermodynamic control.
The template-directed construction of crown-ether-like macrocycles around secondary dialkylammonium ions (R2NH2+) has been utilized for the expedient (one-pot) and high-yielding synthesis of a diverse range of mechanically interlocked molecules. The clipping together of appropriately designed dialdehyde and diamine compounds around R2NH2+-containing dumbbell-shaped components proceeds through the formation, under thermodynamic control, of imine bonds. The reversible nature of this particular reaction confers the benefits of "error-checking" and "proof-reading", which one usually associates with supramolecular chemistry and strict self-assembly processes, upon these wholly molecular systems. Furthermore, these dynamic covalent syntheses exploit the efficient templating effects that the R2NH2+ ions exert on the macrocyclization of the matched dialdehyde and diamine fragments, resulting not only in rapid rates of reaction, but also affording near-quantitative conversion of starting materials into the desired interlocked products. Once assembled, these "dynamic" interlocked compounds can be "fixed" upon reduction of the reversible imine bonds (by using BH3.THF) to give kinetically stable species, a procedure that can be performed in the same reaction vessel as the inital thermodynamically controlled assembly. Isolation and purification of the mechanically interlocked products formed by using this protocol is relatively facile, as no column chromatography is required. Herein, we present the synthesis and characterization of 1) a [2]rotaxane, 2) a [3]rotaxane, 3) a branched [4]rotaxane, 4) a bis [2]rotaxane, and 5) a novel cyclic [4]rotaxane, demonstrating, in incrementally more complex systems, the efficacy of this one-pot strategy for the construction of interlocked molecules.
Self-assembly of dendrimers by slippage.
[reaction: see text] A dendrimer with rotaxane-like characteristics has been assembled under thermodynamic control from complementary wedge-shaped precursors by slippage in CH(2)Cl(2). The driving force for the self-assembly process is the molecular recognition that exists as a result of [N(+)-H.O] and [C-H.O] hydrogen bonds between an NH(2)(+) center in one Fréchet-type benzyl ether wedge and a dibenzo[24]crown-8 unit that links the other two such wedges.
Regulation of Ca2+ release-activated Ca2+ channels by INAD and Ca2+ influx factor.
The coupling mechanism between depletion of Ca(2+) stores in the endoplasmic reticulum and plasma membrane store-operated ion channels is fundamental to Ca(2+) signaling in many cell types and has yet to be completely elucidated. Using Ca(2+) release-activated Ca(2+) (CRAC) channels in RBL-2H3 cells as a model system, we have shown that CRAC channels are maintained in the closed state by an inhibitory factor rather than being opened by the inositol 1,4,5-trisphosphate receptor. This inhibitory role can be fulfilled by the Drosophila protein INAD (inactivation-no after potential D). The action of INAD requires Ca(2+) and can be reversed by a diffusible Ca(2+) influx factor. Thus the coupling between the depletion of Ca(2+) stores and the activation of CRAC channels may involve a mammalian homologue of INAD and a low-molecular-weight, diffusible store-depletion signal.