Synthesis of Iodoaminoimidazole Arabinoside (IAIA): A Potential Reductive Metabolite of the Spect Imaging Agent,Iodoazomycin Arabinoside (IAZA)

Abstract

The stereospecific synthesis of 1-(5-deoxy-5-iodo-α-D-arabino-furanosyl)-2-aminoimidazole (iodoaminoimidazole arabinoside: IAIA, 2) is described. The reaction of the protected sugar bromide (8) and trifluoroacetamidoimidazole (10B) gave the coupled product (11B), which gave the free nucleoside (4) on deblocking. It was identical with AIA obtained by reduction of AZA (azomycin arabinoside), whose anomeric configuration was found to be a by the X-ray crystallography.     

Growth factor transgenes interactively regulate articular chondrocytes

Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin‐like growth factor I (IGF‐I), fibroblast growth factor‐2 (FGF‐2), transforming growth factor beta1 (TGF‐β1), bone morphogenetic protein‐2 (BMP‐2), and bone morphogenetic protien‐7 (BMP‐7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF‐I and FGF‐2 maximized cell proliferation. The three‐transgene group encoding IGF‐I, BMP‐2, and BMP‐7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell‐based articular cartilage repair. J. Cell. Biochem. 114: 908–919, 2013. © 2012 Wiley Periodicals, Inc.     

A dynamic spatiotemporal extracellular matrix facilitates epicardial-mediated vertebrate heart regeneration

Unlike humans, certain adult vertebrates such as newts and zebrafish possess extraordinary abilities to functionally regenerate lost appendages and injured organs, including cardiac muscle. Here, we present new evidence that a remodeled extracellular matrix (ECM) directs cell activities essential for cardiac muscle regeneration. Comprehensive mining of DNA microarrays and Gene Ontology term enrichment analyses for regenerating newt and zebrafish hearts revealed that distinct ECM components and ECM-modifying proteases are among the most significantly enriched genes in response to local injury. In contrast, data analyses for mammalian cardiac injury models indicated that inflammation and metabolic processes are the most significantly activated gene groups. In the regenerating newt heart, we show dynamic spatial and temporal changes in tenascin-C, hyaluronic acid, and fibronectin ECM distribution as early as 3 days postamputation. Linked to distinct matrix remodeling, we demonstrate a myocardium-wide proliferative response and radial migration of progenitor cells. In particular, we report dramatic upregulation of a regeneration-specific matrix in the epicardium that precedes the accumulation and migration of progenitor cells. For the first time, we show that the regenerative ECM component tenascin-C significantly increases newt cardiomyocyte cell cycle reentry in vitro. Thus, the engineering of nature-tested extracellular matrices may provide new strategic opportunities for the enhancement of regenerative responses in mammals.     

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.     

Natural and Regenerated Saltmarshes Exhibit Similar Soil and Belowground Organic Carbon Stocks,Root Production and Soil Respiration

Ecosystems - Saltmarshes provide many valuable ecosystem services including storage of a large amount of ‘blue carbon’ within their soils. To date, up to 50% of the world’s...     

Placental metabolite profiles in late gestation for healthy mice

Metabolomics - The study of lipoprotein metabolism at the population level can provide valuable information for the organisation of lipoprotein related processes in the body. To use this...     

Enhancement by serotonin of the growth in vitro of antennal lobe neurons of the sphinx moth Manduca sexta

Cell culture experiments have been used to examine the effects of serotonin [5-hydroxytryptamine (5-HT)] on the morphological development of antennal lobe (AL) neurons in the brain of the sphinx moth, Manduca sexta. The majority of cells used in this study were from animals at stage 5 of the 18 stages of metamorphic adult development. 5-HT did not affect the survival of M. sexta AL neurons in culture, but did increase the numbers of cells displaying features characteristic of certain cell types. Three morphologically distinct cell types were examined in detail. The principal effect of 5-HT on these neurons was enhancement of cell growth. The magnitude of responses to this amine was cell-type specific. Site-specific responses to 5-HT were apparent also in one cell type. Our results suggest that the effects of 5-HT can change during the course of metamorphic development. These changes coincide temporally with the development of fast, sodium-based action potentials. © 1996 John Wiley & Sons, Inc.     

The development of resistance to the lipogenic effects of insulin in brown and white adipose tissue of spontaneously type II diabetic male CBA/Ca mice.

1. Lipogenesis in brown adipose tissue and white adipose tissue (WAT) was measured in vivo in spontaneously type II diabetic male CBA/Ca mice. 2. Lipogenic rates rose sharply in brown adipose tissue between the third and fourth month of life, concomitant with the onset of hyperinsulinaemia. However, lipogenic rates fell between the fourth and fifth month of age, and remained low, despite increasing circulating insulin concentrations. 3. Lipogenesis in white adipose tissue showed a modest response to hyperinsulinaemia followed by increasing resistance to elevated insulin concentrations after 5 months of age. 4. Studies involving either the injection of insulin or the intubation of glucose provided further evidence for the development of insulin resistance in both brown and white adipose tissue.     

Thermogenic responses to body cooling during fever induced by Staphylococcus aureus cell walls in rabbits

Hypothalamic temperature (T _hypo) and metabolic heat production (M) were measured in seven conscious rabbits injected intravenously with either saline or with Staphylococcus aureus, (8 · 10⁷ cell walls · kg⁻¹) while being subjected to a 3-h period of ramp-like total body cooling using a chronically implanted intravascular heat exchanger. In pyrogen-injected animals cooling started (1) at the time of injection or (2) 70 min after injection. In (1) the fall in T _hypo induced by heat extraction was similar (1.0 °C) in afebrile and febrile animals. In (2) there was a transient increase in T _hypo of about 0.5 °C at a time corresponding to the start of fever resulting in a significantly smaller fall in T _hypo at the end of the 3-h cooling period (0.5 °C vs 0.9 °C, P < 0.05, n = 5). At this time in both (1) and (2) M was lower than theoretically expected from the increase in shivering threshold during fever. However, most of this effect can be explained when available data showing a decrease in thermosensitivity during S. aureus-induced fever are taken into account. After cessation of cooling in both groups of febrile animals T _hypo rose to about 1 °C higher than the precooling level, which is comparable to the fever level in a separate series of experiments with S. aureus injection without cooling (1.2 °C). Accepted: 23 September 1997     

Expression of thymidine kinase and dihydrofolate reductase genes in mammalian ts mutants of the cell cycle

Thymidine kinase and dihydrofolate reductase mRNA levels and enzyme activities were determined in two temperature-sensitive cell lines, tsAF8 and ts13, that growth arrest in the G1 phase of the cell cycle at the restrictive temperature. The levels of thymidine kinase mRNA and enzyme activity increased markedly in both cell lines serum stimulated from quiescence at the permissive temperature. At the nonpermissive temperature, the levels of thymidine kinase mRNA and enzyme activity remain at the low levels of quiescent G0 cells. The levels of dihydrofolate reductase mRNA as well as the enzyme activity also increase when both cell lines are serum stimulated at the permissive temperature. When ts13 cells are serum stimulated at the nonpermissive temperature dihydrofolate reductase enzyme activity declines rapidly and dihydrofolate reductase mRNA is below detectable levels. On the contrary, when tsAF8 cells are serum stimulated at the nonpermissive temperature dihydrofolate reductase enzyme activity increases and mRNA levels are detectable slightly above G0 levels, even though the cells are blocked in the G1 phase. Studies with 2 other cDNA clones (one with an insert whose expression is cell cycle dependent and the other with an insert whose expression is not cell cycle dependent) indicate that the results are not due to aspecific toxicity or the effect of temperature. We conclude that the expression of different genes is affected differently by the ts block in G1, even when these genes are all growth-related.