Proteoglycans mechanism

Garcia-Manyes S, Bucior 1, Ros R, Anselmetti D, Sanz F, Burger MM, Fernandez-Busquets X. Proteoglycan mechanics studied by single-molecule force spectroscopy of allotypic cell adhesion gly-cans. J. Biol. Chem. 2006 281 5992-5999. 

The syndecan family of heparin sulfate proteoglycans (HSPGs) plays critical roles in several signal transduction pathways, and syndecan 3 intramembrane proteolysis is presenilin/y-secretase dependent (357). COX2 and COXl potentiate ABP formation through mechanisms that involve y-secretase activity. Sulindac sulfide and other NSAIDs (ibuprofen, indomethacin, R-flurbiprofen) selectively decrease the secretion of ABP independently of COX activity, probably via y-secretase inhibition (358-360). Pepstatin A methylester, sulfonamides, and benzodiazepines can also act as potent, noncompetitive, y-secretase inhibitors (335). These are but a few examples of the potential repercussions and biochemical consequences that the pharmacological manipulation of secretases in AD may bring about. 

The rationale for this type of contrast agent is to use the endogenous metabolic pathway of lipid metabolism in the liver for the transport of iodinated substances. Chylomicron remnants are naturally occurring lipoproteins in the blood that are responsible for the transport of lipids into the liver. Three different mechanisms for this transport are discussed direct uptake by the low-density lipoprotein receptor transport to the low-density lipoprotein receptor-related protein (LRP) mediated by heparan sulfate proteoglycan (HSPG) or direct HSPG-LRP uptake and direct HSPG uptake. One of the prerequisites for particles to be transported by these mechanisms is a mean diameter of less than 100-300 run. 

Various types of proteins have been purified using hydrophobic interaction chromatography including alkaline phophatase, estrogen receptors, isolectins, strepavidin, calmodulin, epoxide hydrolase, proteoglycans, hemoglobins, and snake venom toxins (46). In the case of cobra venom toxins, the order of elution of the six cardiotoxins supports the hypothesis that the mechanism of action is related to hydrophobic interactions with the phospholipids in the membrane. 

A passive flux of water continually flows across the endothelial layer toward the stroma, which has a tendency to swell. An active pump mechanism pulls an aqueous flux in the opposite direction which controls corneal turgescence [13]. Corneal deturgescence is an ATP-dependent process of the endothelial cells and as such any disruption of the endothelium may result in corneal oedema, thereby affecting corneal transparency. The specific distribution of different proteoglycans across the cornea has recently been implicated in water gradients across the cornea. This water gradient serves to diminish dehydration of the front of the cornea, which is exposed to the atmosphere. 

The presence of proteoglycans in the extrafibrillar compartment would result in water depletion in the intrafibrillar compartment when the salinity of the synovial joint, or of the bath in laboratory experiments, is decreased. Therefore there should be mechanisms that retain intrafibrillar water within fibrils. Here, hydration forces that act at short distances, a few angstroms, are postulated to be the main factor that limit the exchangeability of intrafibrillar water. 

As already mentioned, the definition of phases in articular cartilage is not unambiguous, because the mechanical, chemical and electrical roles of proteoglycans (PG s) may dictate contradictory choices. In fact, if the phase criterion was kinematically based (that is on velocity), PG s would be classified as part of the solid phase. However, its osmotic effect is important, not so much because of its concentration or molar fraction itself, but because of its effective charge and the latter should be involved in the electroneutrality condition of the extrafibrillar phase. 

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