Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The formation and structure of the complement cytolytic intermediary complex, C5b-7, were studied with the aim of determining the interactive regions of C5, C6, and C7. The structure of human complement component C5 was elucidated by the application of limited proteolysis which generated well characterized major polypeptide fragments of this molecule. Plasmin, thrombin, and kallikrein cleave C5b with greater facility than C5. The most useful cleavage of C5b was effected by plasmin because the fragmentation pattern was similar to the processing of C3b by factors H, I, and kallikrein. Plasmin hydrolyzes peptide bonds within the alpha'-chain of C5b, resulting in a four-chain fragment, C5c (M(r) = 142,000), and a single chain fragment, C5d (M(r) = 43,000). Circular dichroism spectroscopic analyses indicated that C5d is substantially richer in alpha-helical content than is C5c (27 versus 9%). Polyclonal antibodies directed against C5c blocked the interaction of C5b-6 with C7, whereas antibodies directed against C5d inhibited the binding of C5 with C3b. Chemical cross-linking using a cleavable radioiodinated photoreactive reagent revealed that both C6 and C7 associate preferentially with the alpha'-chain of C5b. The reversible interactions of C5 with C6, C7, and major polypeptide fragments derived from these were investigated with solid phase binding assays. The results indicate that the carboxyl-terminal domains of C6 and C7, which have cysteine-rich modules homologous to those found in factors H and I, have the capacity to link specifically with C5.
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PMID:Formation and structure of the C5b-7 complex of the lytic pathway of complement. 138 99

The aim of this crossover clinical study was to gain basic information on the hemocompatibility and effectiveness of recently developed high-flux membranes made of cuprammonium rayon with ultrafiltration coefficients of 10, 17, and 19 ml/mm Hg/h (S12W, SU12W, and SS12W dialyzers, respectively), and to identify any possible differences from a conventional membrane made of the same material with an ultrafiltration coefficient of 6 ml/mm Hg/h (C12W dialyzer). All the tested membranes led to an abrupt drop in leukocyte count in the initial phase of hemodialysis. In high-flux membranes, C5a anaphylatoxin would pass into the dialysate, but mean C5a anaphylatoxin concentrations in the dialysate were lower by orders of magnitude than its plasma concentrations, which behaved, in high- and low-flux membranes alike, typically of those made of nonsubstituted cellulose with no intermembrane differences. As judged by the concentrations of the thrombin-antithrombin III complex, the coagulation system was activated--again, without differences between membranes. The reduction rates for urea, creatinine, and phosphates were comparable for all the tested membranes. Compared with baseline, the post-dialysis serum concentrations of beta 2-microglobulin in high-flux membranes, unlike the low-flux membrane, were significantly lower. We conclude that there are no significant differences between the tested high- and low-flux membranes made of cuprammonium rayon in the monitored hemocompatibility parameters, and that high-flux membranes are capable of reducing serum beta 2-microglobulin concentrations.
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PMID:Clinical study of high-flux cuprammonium rayon hemodialysis membranes. 811 71

Increased microvascular dilatation and permeability is observed during allograft rejection. Because vascular integrity is an important indicator of transplant health, we have sought to limit injury to blood vessels by blocking complement activation. Although complement component 3 (C3) inhibition is known to be vasculoprotective in transplantation studies, we recently demonstrated the paradoxical finding that, early in rejection, C3(-/-) transplant recipients actually exhibit worse microvascular injury than controls. In the genetic absence of C3, thrombin-mediated complement component 5 (C5) convertase activity leads to the generation of C5a (anaphylatoxin), a promoter of vasodilatation and permeability. In the current study, we demonstrated that microvessel thrombin deposition is significantly increased in C3(-/-) recipients during acute rejection. Thrombin colocalization with microvessels is closely associated with remarkably elevated plasma levels of C5a, vasodilatation, and increased vascular permeability. Administration of NOX-D19, a specific C5a inhibitor, to C3(-/-) recipients of airway transplants significantly improved tissue oxygenation, limited microvascular leakiness, and prevented airway ischemia, even in the absence of conventional T-cell-directed immunosuppression. As C3 inhibitors enter the clinics, the simultaneous targeting of this thrombin-mediated complement activation pathway and/or C5a itself may confer significant clinical benefit.
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PMID:Targeting complement component 5a promotes vascular integrity and limits airway remodeling. 2353 Feb 12