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Wednesday, November 01, 2017 10:27:04 AM
Current main hypothesis describes a scramblase activity to be responsible for PS appearance at the cell surface. Scramblase translocates phospholipids bidirectionally over the two leaflets of the PM thereby collapsing PS asymmetry. Scrambling is rapid, ATP-independent and non-selective for phospholipid species and it causes randomization of the phospholipids over the two membrane leaflets. Scramblase has been demonstrated to operate in erythrocytes [14], activated platelets [15] and apoptotic cells [16]. Several studies have tried to identify the protein(s) that scramble the phospholipids of the PM. Isolation and reconstitution experiments delivered the protein phospholipid scramblase 1 (PLSCR1), which is the most serious candidate up to now [17]. Closer inspection, however, casted doubt because cells were able to scramble PM phospholipids in the absence of PLSCR1 [18] and six different cell lines showed a lack of correlation between the level of PLSCR1 expression and the capacity to externalize PS during apoptosis [19]. No other candidates are proposed as yet indicating complexity of phospholipid scrambling and, likely, diversity in scrambling mechanisms. The latter is illustrated by the finding that platelets of a patient with Scott syndrome fail to express PS upon Ca2+-ionophore treatment (a trigger for healthy platelets to expose PS) whilst Scott B-cells normally translocate PS to the cell surface upon execution of apoptosis [20].
Recently an alternative hypothesis was postulated that describes PS externalization as part of membrane repair mechanisms that start to operate during apoptosis and involve fusion of lysosomes with PM [21]. This hypothesis does not require the action of a scramblase protein.
Translocation of PS to the PM exoplasmic leaflet proceeds without compromising the barrier function of the PM. Once in the exoplasmic leaflet PS may participate in a variety of processes depending on type and localization of the PS exposing cell. Circulating erythrocytes for example gradually express PS during aging. PS at the erythrocyte surface functions as an ‘eat me’ signal towards the reticuloendothelial system, which clears the PS tagged erythrocytes from the circulation by phagocytosis [22]. Platelets can participate in hemostatic and thrombotic processes and while doing so can expose PS at their surface. The PS expressing surface catalyzes coagulation reactions that culminate in the formation of thrombin, which subsequently stabilizes the platelet thrombus by generation of fibrin [23]. Activated macrophages that are engaged to engulf dying cells expose PS at their surface. Inhibition of PS exposure greatly impairs phagocytic capacity of the activated macrophage [24]. Vaccinia virus presents PS at the viral membrane to activate PS dependent macropinocytosis with subsequent infection of the host cell [25]. Macrophages and fibroblasts that are infected with Pichinde Virus express PS at the cell surface [26].
The most important and abundant cellular process that is accompanied by cell surface expression of PS is apoptosis, a biochemically regulated process of cell suicide [27]. Firstly described for apoptotic lymphocytes [13] PS exposure is now appreciated as a ubiquitous phenomenon of apoptosis that is independent of cell type and cell death inducing trigger [28] and that is phylogenetically conserved [29]. PS on the surface of an apoptotic cell is one of the most important ‘eat me’ flags that not only triggers engulfment but also activates signaling pathways that control cholesterol efflux and expression of anti- and pro-inflammatory cytokines [30]. In addition, PS on the apoptotic cell surface is involved in regulation of immune response towards antigens of the apoptotic cell [31]. Cells that die by executing a non-apoptotic cell death program also activate a machinery that drives cells surface expression of PS [32] indicating that PS expression is an important phenomenon in dealing with cell death in the context of the multicellular organism. Recognition and engulfment of PS expressing cells are extremely efficient in healthy tissues, which therefore contain, if any, a low steady state level of PS expressing cells. Pathologies can change drastically the balance between appearance and clearance of PS expressing cells towards a sustained presence of PS expressing cells and cell remnants such as apoptotic bodies and cell derived microparticles in diseased tissue. As such surface expressed PS is potentially an informative biomarker for diagnosing disease and evaluating efficacy of therapy. In addition cell surface expressed PS may serve as a target for TDD strategies to deliver therapeutic compounds specifically to diseased tissue.
PS binding ligands
In order to exploit fully the potential of PS as a target for Molecular Imaging (diagnosis) and TDD (therapy) ligands should be available that bind selectively and with high affinity to cell surface expressed PS in the complexity of the multicellular organism. To date a variety of PS-binding compounds have been reported in the literature including proteins [2], peptides [33–36] and small chemical entities [37].
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Remember, any and all patents derived from USING PS Targeting patents will have only been made possible to know, based upon collaborations with Peregrine Pharmaceuticals
How many undisclosed collaborations.....are now required to be known and verify patents that have followed where one only then knows which protein pathways etc etc to target in on....
Fiduciary duty so must be met
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