1,200 research outputs found
DESIGN, SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF RIGID ANALOGUES OF THE NICOTINIC AGONIST 1,1-DIMETHYL-4-PHENYLPIPERAZINIUM IODIDE (DMPP)
Vascular tube formation on matrix metalloproteinase-1-damaged collagen
Connective tissue damage and angiogenesis are both important features of tumour growth and invasion. Here, we show that endothelial cells maintained on a three-dimensional lattice of intact polymerised collagen formed a monolayer of cells with a cobblestone morphology. When the collagen was exposed to organ culture fluid from human basal cell tumours of the skin (containing a high level of active matrix metalloproteinase-1 (MMP-1)), degradation of the collagen matrix occurred. The major degradation products were the - and -sized fragments known to result from the action of MMP-1 on type I collagen. When endothelial cells were maintained on the partially degraded collagen, the cells organised into a network of vascular tubes. Pretreatment of the organ culture fluid with either tissue inhibitor of metalloproteinase-1 (TIMP-1) or neutralising antibody to MMP-1 prevented degradation of the collagen lattice and concomitantly inhibited endothelial cell organisation into the vascular network. Purified (activated) MMP-1 duplicated the effects of skin organ culture fluid, but other enzymes including MMP-9 (gelatinase B), elastase or trypsin failed to produce measurable fragments from intact collagen and also failed to promote vascular tube formation. Together, these studies suggest that damage to the collagenous matrix is itself an important inducer of new vessel formation
Cyclic stretching of mesangial cells up-regulates intercellular adhesion molecule-1 and leukocyte adherence: A possible new mechanism for glomerulosclerosis
Intraglomerular hypertension is a primacy causal factor in the progressive glomerulosclerosis that characterizes diabetic nephropathy or severe renal ablation. However, inflammation of the glomerular mesangium also participates in at least the early phase of these diseases. In glomerulonephritis, where inflammation is thought to be the predominant causal factor, intraglomerular hypertension is also often present. Mesangial cells (MCs) are critical in orchestrating key functions of the glomerulus including extracellular matrix metabolism, cytokine production, and interaction with leukocytes. Because MCs are subject to increased stretching when intraglomerular hypertension is present, and in glomerulonephritis MC/leukocyte interactions seem to be mediated primarily via the up-regulation of intercellular adhesion molecule-1 (ICAM-1), we examine the possibility that cyclic stretching is a stimulus for increased MC ICAM-1 activity. We demonstrate that the normal low levels of MC ICAM-1 mRNA and protein are dramatically up-regulated by even short intervals of cyclic stretch. This effect is dose- and time-dependent, and requires little amplitude and a brief period of elongation for significant induction. Stretch-induced MC ICAM-1 also leads to a marked elevation in phagocytic leukocyte adherence. This stimulated adherence is equal or greater than that induced by the inflammatory cytokine tumor necrosis factor-α, whereas an additive effect occurs when both are applied in combination. Our results indicate that stretch-induced ICAM-1 may provide a direct link between hypertension and inflammation in the progression of injury and glomerulosclerosis in diabetes, renal ablation, and other forms of glomerulonephritis. © 2001 American Society for Investigative Pathology
Anomalous crossover between thermal and shot noise in macroscopic diffusive conductors
We predict the existence of an anomalous crossover between thermal and shot
noise in macroscopic diffusive conductors. We first show that, besides thermal
noise, these systems may also exhibit shot noise due to fluctuations of the
total number of carriers in the system. Then we show that at increasing
currents the crossover between the two noise behaviors is anomalous, in the
sense that the low frequency current spectral density displays a region with a
superlinear dependence on the current up to a cubic law. The anomaly is due to
the non-trivial coupling in the presence of the long range Coulomb interaction
among the three time scales relevant to the phenomenon, namely, diffusion,
transit and dielectric relaxation time.Comment: 4 pages, 2 figure
Shot-noise anomalies in nondegenerate elastic diffusive conductors
We present a theoretical investigation of shot-noise properties in
nondegenerate elastic diffusive conductors. Both Monte Carlo simulations and
analytical approaches are used. Two new phenomena are found: (i) the display of
enhanced shot noise for given energy dependences of the scattering time, and
(ii) the recovery of full shot noise for asymptotic high applied bias. The
first phenomenon is associated with the onset of negative differential
conductivity in energy space that drives the system towards a dynamical
electrical instability in excellent agreement with analytical predictions. The
enhancement is found to be strongly amplified when the dimensionality in
momentum space is lowered from 3 to 2 dimensions. The second phenomenon is due
to the suppression of the effects of long range Coulomb correlations that takes
place when the transit time becomes the shortest time scale in the system, and
is common to both elastic and inelastic nondegenerate diffusive conductors.
These phenomena shed new light in the understanding of the anomalous behavior
of shot noise in mesoscopic conductors, which is a signature of correlations
among different current pulses.Comment: 9 pages, 6 figures. Final version to appear in Phys. Rev.
Characterization of adenosine receptors in bovine chondrocytes and fibroblast-like synoviocytes exposed to low frequency low energy pulsed electromagnetic fields
SummaryObjectiveThe present study describes the presence and binding parameters of the A1, A2A, A2B and A3 adenosine receptors in bovine chondrocytes and fibroblast-like synoviocytes. The effect of low frequency low energy pulsed electromagnetic fields (PEMFs) on the adenosine receptor affinity and density was studied.MethodsSaturation, competition binding experiments and Western blotting assays in the absence and in the presence of PEMFs on the adenosine receptors in bovine chondrocytes or fibroblast-like synoviocytes were performed. Thermodynamic analysis of the A2A or A3 binding was studied to investigate the forces driving drug–receptor coupling. In the adenylyl cyclase and proliferation assays the potency of typical high-affinity A2A or A3 agonists in the absence and in the presence of PEMFs was evaluated.ResultsBovine chondrocytes and fibroblast-like synoviocytes expressed all adenosine receptors. PEMFs evoked an up-regulation of A2A and A3 receptors and thermodynamic parameters indicate that adenosine binding is enthalpy and entropy driven. In PEMF-treated cells the potency of typical A2A or A3 agonists on cyclic AMP assays was significantly increased when compared with the untreated cells. PEMFs potentiated the effect of A2A or A3 agonists on cell proliferation in both cell types.ConclusionsPEMFs mediate an up-regulation of A2A and A3 receptors related to an increase of their functional activities in bovine chondrocytes and fibroblast-like synoviocytes. No differences are present in adenosine affinity and in the drug–receptor interactions. Our data could be used as a trigger to future studies addressed to PEMFs and adenosine therapeutic intervention in inflammatory joint diseases
Pharmacological characterization of P2X1 and P2X3 purinergic receptors in bovine chondrocytes
SummaryObjectiveThe aim of the present study is that of characterizing, for the first time in a quantitative way, from a biochemical, physico chemical and functional point of view P2X1 and P2X3 purinergic receptors in bovine chondrocytes. The affinity and the potency of typical purinergic ligands were studied through competition binding experiments and their role in modulating chondrocyte actvities was investigated by analyzing nitric oxide (NO) and prostaglandin E2 (PGE2) release.MethodsSaturation, competition binding experiments, western blotting and immunohistochemistry assays on the P2X1 and P2X3 purinergic receptors in bovine chondrocytes were performed. Thermodynamic analysis of the P2X1 and P2X3 purinergic binding was studied to investigate the forces driving drug-receptor coupling. In the functional assays (NO and PGE2 release) the potency of purinergic agonists and antagonists was evaluated.ResultsBovine chondrocytes expressed P2X1 and P2X3 purinergic receptors and thermodynamic parameters indicated that purinergic binding is enthalpy- and entropy-driven for agonists and totally entropy-driven for antagonists. Typical purinergic agonists such as adenosine 5′-triphosphate (ATP) and α,β-methyleneATP were able to increase NO and PGE2 release. A purinergic antagonist, A317491, was able to block the stimulatory effect on functional experiments mediated by the agonists.ConclusionsThese data demonstrate for the first time the presence of functional P2X1 and P2X3 purinergic receptors in bovine chondrocytes. Agonists and antagonists are thermodynamically discriminated and are able to modulate functional responses such as NO and PGE2 release. These results suggest the potential role of novel purinergic antagonists in the treatment of pathophysiological diseases linked to the inflammation and involved in articular cartilage resorption
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