Guanylyl cyclase-dependent chemotaxis of endothelial cells in response to nitric oxide gradients

Nitric oxide (NO) is an important regulator of angiogenesis and neovascularization. The nature of endothelial cell motility responses to NO was examined using a Boyden chamber method. NO generated via decomposition of either DEA/NO or DETA/NO produced increases in human umbilical vein endothelial cell (HUVEC) chemotaxis, which were completely abrogated by ODQ, a soluble guanylyl cyclase inhibitor. Measurements of NO either directly by chemiluminescence or its chemistry with diaminofluorescein revealed that chemotaxis was driven by subtle NO gradients between the lower and the upper wells in this system. In addition to diffusion and volatilization from the upper chambers, the data showed that HUVEC consumption of NO contributed to these sustained gradients. Comparison of DEA/NO- and DETA/NO-mediated responses suggested that the persistence of spatial NO gradients is as significant as the absolute magnitude of NO exposure per unit time. The findings suggest that subnanomolar NO gradients are sufficient to mobilize endothelial cell migration into hypoxic tissue during neovascularization events, such as in wound healing and cancer.     

A review of the effects of supplementary nutrition in the ewe on the concentrations of reproductive and metabolic hormones and the mechanisms that regulate folliculogenesis and ovulation rate

This paper discusses the phenomenon of nutritional flushing in ewes whereby increased nutrition stimulates folliculogenesis and ovulation rate. In addition the paper reviews recent findings on the effects of increased levels of nutrition on the blood concentrations of reproductive and metabolic hormones in the ewe and some of the intraovarian changes that take place in response to nutritional stimulation. Finally, in the paper, we propose a model of the physiological mechanism for the nutritional stimulation of folliculogenesis and we review how closely the model fits recent published and unpublished evidence examining the mechanism of flushing. Nutritional stimulation alters the blood concentrations of some metabolic hormones. By using short-term models of nutritional flushing, we have shown that as the blood concentrations of insulin and leptin increase that of growth hormone decreases while that of IGF-I appears unaffected by the nutritional flushing. Nutritional flushing also alters the blood concentrations of some reproductive hormones. Again, using the same model, we have shown that there is a transient increase in FSH and a decrease in oestradiol concentrations in the blood. The changes in oestradiol are particularly evident in the follicular phase of the oestrous cycle. In the ovary, the effect of nutrition is to stimulate folliculogenesis. These changes are associated with intra-follicular alterations in the insulin-glucose, IGF and leptin metabolic systems. The stimulation of these intra-follicular systems leads to a suppression in follicular oestradiol production. The consequence of these direct actions on the follicle is a reduced negative feedback to the hypothalamic-pituitary system and increased FSH secretion that leads to a stimulation of folliculogenesis.     

A new class of bradykinin 1 receptor antagonists containing the piperidine acetic acid tetralin core

The bradykinin 1 (B1) receptor is upregulated during times of inflammation and is important for maintaining inflamed and chronic pain states. Blocking this receptor has been shown to reverse and/or ameliorate pain and inflammation in animal models. In this report, we describe a new class of B1 receptor antagonists that contain the piperidine acetic acid tetralin core. A structure-activity relationship for these analogs is described in this paper. The most potent compounds from this class have IC50s<20 nM in a B1 receptor functional assay. One of these compounds, 13g, shows modest oral bioavailability in rats.     

Design and synthesis of novel N-sulfonyl-2-indole carboxamides as potent PPAR-gamma binding agents with potential application to the treatment of osteoporosis

The synthesis and structure-activity relationships of a novel series of N-sulfonyl-2-indole carboxamides that bind to peroxisome proliferator-activated receptor gamma (PPAR-gamma) are reported. Chemical optimization of the series led to the identification of 4q (IC(50)=50 nM) as a potent binding agent of PPAR-gamma. Also reported is preliminary cell based data suggesting the use of these compounds in the treatment of osteoporosis.     

Structure-activity relationships of triazolopyridine oxazole p38 inhibitors: identification of candidates for clinical development

The synthesis, structure-activity relationship, in vivo activity, and metabolic profile for a series of triazolopyridine-oxazole based p38 inhibitors are described. The deficiencies of the lead structure in the series, CP-808844, were overcome by changes to the C4 aryl group and the triazole side-chain culminating in the identification of several potential clinical candidates.     

New bicyclic cannabinoid receptor-1 (CB1-R) antagonists

A series of conformationally constrained bicyclic derivatives derived from SR141716 was prepared and evaluated as hCB(1)-R antagonists and inverse agonists. Optimization of the structure-activity relationships around the 2,6-dihydro-pyrazolo[4,3-d]pyrimidin-7-one derivative 2a led to the identification of two compounds with oral activity in rodent feeding models (2h and 4a). Replacement of the PP group in 2h with other bicyclic groups resulted in a loss of binding affinity.     

Reduced performance of native infauna following recruitment to a habitat-forming invasive marine alga

Despite well-documented negative impacts of invasive species on native biota, evidence for the facilitation of native organisms, particularly by habitat-forming invasive species, is increasing. However, most of these studies are conducted at the population or community level, and we know little about the individual fitness consequences of recruitment to habitat-forming invasive species and, consequently, whether recruitment to these habitats is adaptive. We determined the consequences of recruitment to the invasive green alga Caulerpa taxifolia on the native soft-sediment bivalve Anadara trapezia and nearby unvegetated sediment. Initially, we documented the growth and survivorship of A. trapezia following a natural recruitment event, to which recruitment to C. taxifolia was very high. After 12 months, few clams remained in either habitat, and those that remained showed little growth. Experimental manipulations of recruits demonstrated that all performance measures (survivorship, growth and condition) were significantly reduced in C. taxifolia sediments compared to unvegetated sediments. Exploration of potential mechanisms responsible for the reduced performance in C. taxifolia sediments showed that water flow and water column dissolved oxygen (DO) were significantly reduced under the canopy of C. taxifolia and that sediment anoxia was significantly higher and sediment sulphides greater in C. taxifolia sediments. However, phytoplankton abundance (an indicator of food supply) was significantly higher in C. taxifolia sediments than in unvegetated ones. Our results demonstrate that recruitment of native species to habitat-forming invasive species can reduce growth, condition and survivorship and that studies conducted at the community level may lead to erroneous conclusions about the impacts of invaders and should include studies on life-history traits, particularly juveniles.