Bound toxins

Contrary to carbon enterosorbents, Enterosgel does not possess an ability for selective removal of albumin-bound ligands regardless of their affinity with the protein carrier - weak (L-tryptophane), medium (sodium caprylate, deoxycholic acid), or strong (indole-3-carboxylic acid and unconjugated bilirubin). It means that if protein-bound toxins are removed by Enterosgel, this occurs simultaneously with adsorption of the carrier protein. 

Sarnatskaya V, Yushko L, Nikolaev A et al (2007) New approaches to the removal of protein-bound toxins from blood plasma of uremic patients. Artif Cells Blood Substit ImmobU Biotechnol 3 287-308... 

Deliganding Carbonic Adsorbents for Simultaneous Removal of Protein-Bound Toxins, Bacterial Toxins and Inflammatory Cytokines... 

Keywords Uremic toxins Protein bound toxins... 

One should also consider that protein-bound toxins, due to their hydrophobicity can easily pass through a lipoprotein cell membrane acting directly on intracellular structures. 

Essentially the same reaction patterns were demonstrated with the VCS method where the bound toxin was directly visualized, thus avoiding the possible influence of any subsequent immunoreaction steps. Tetanus toxin gave positive, "wet" reactions with the same gangliosides that were positive in the ELISA method, i.e. GTlb,... 

Artificial liver support systems aim at the extracorporeal removal of water soluble and protein-bound toxins (albumin being the preferential binding protein) associated with hepatic failure. Albumin contains reversible binding sites for substances such as fatty acids, hormones, enzymes, dyes, trace metals and drugs [26] and therefore helps elimination by kidneys of substances that are toxic in the unbound state. It should be noticed that the range of substances to be removed is broad and not completely identified. Clinical studies showed that the critical issue of the clinical syndrome in liver failure is the accumulation of toxins not cleared by the failing liver. Based on this hypothesis, the removal of lipophilic, albumin-bound substances, such as bilirubin, bile adds, metabolites of aromatic amino acids, medium-chain fatty acids, and cytokines, should be benefidal to the dinical course of a patient in liver failure. 

For this purpose, the removal procedures are mainly based on membrane separation that ideally should bring free and bound toxins to a nonspedfic adsorption device (ion-exchangers and/or activated charcoal). Blood should not perfuse directly such components, due to bioincompatibity aspeds. Therefore, several processes have been proposed to correctly handle toxins carried by plasma [27]. They are described in the following sections. All of them need a physical barrier between the blood cells and the adsorption system. This physical sieve is always a membrane with adequate properties, through which toxins can be transferred by diffusion or convection. 

F. Bound Toxins. Another approach to more environmentally acceptable preservatives is to chemically bond a toxic compound onto a wood component so that it cannot be leached out. The compound, once reacted, would have to retain its toxic properties. Compounds now used as wood preservatives are toxic to the organism because they are ingested by the organism. If the toxic compound were bound to the wood, they may be toxic to the organism only when ingested. Because of this, the approach of permanently bound toxins may not be a fruitful research area. 

It is also possible to react acid chlorides (20) or anhydride-containing compounds so as to form ester bonds with hydroxyl groups on one of the wood components. Ester bonds could slowly hydrolyze and release the bound toxin. In this case, the release of the preservatives would be a function of the rate of hydrolysis and not directly related to weathering effects (for example, water solubility, vapor pressure, UV degradation, etc.). Controlled release fungicides based either on slow hydrolysis or capsule erosion could greatly decrease the quantity of preservative needed to adequately protect a wooden structure, since leaching could be controlled. 

However, other cells may respond differently to the toxin. In particular, platelets are able to resist the entry of pertussis toxin, either because they lack surface binding sites for the toxin B oligomer or because they are unable to internalize the bound toxin (Brass et al., 1990). PT-sensitive G proteins expressed in insect Sf9 cells (ovary cells from the insect Spodoptera frugiperda Sf9 cells are employed as an overexpression system for G proteins and other signal transduction components by infection with recombinant baculovirus) are also not modified by the toxin (Mulheron et al., 1994). 

The extreme toxicity of clostridial neurotoxins (CNTs) derives from their absolute neurospecificity as well as from catalytic activity. TeTx and BoNTs bind specifically to the neuromuscular junction (NMJ) of motor neurons. The identity of the receptor(s) on the presynaptic membrane is unknown, but their extreme toxicity suggests that the binding affinity to the cognate receptor must be very high. The receptor-bound toxin is internalized at the presynaptic membrane of the NMJ and gains access to the neuronal cytosol. Here it blocks the release of acetylcholine (ACh), causing a flaccid paralysis (Simpson,... 

Entry of the toxin into the nerve terminal Both TeTx and BoNTs enter the nervous system preferentially at the neuromuscular junction. Bound toxins are internalized by the nerve terminal, by means of endocytosis. This process requires energy and probably delivers the toxin to an endosomal compartment within the terminal. H chains mediate specific binding, internalization and intra-neuronal sorting (Niemann, 1991). 

The next step in the entry process is endocytic uptake of the bound toxin. The uptake is comparatively slow and appears to occur from clathrin-coated pits (Morris ef al., 1985). Once in endosomes, the toxin is exposed to acidic conditions a pH below 5.3 is necessary for the penetration to the cytosol (Sandvig and Olsnes, 1981). If acidification of the endosomes is prevented by exposure of the cells to NH4CI or monensin, the cells are protected from poisoning. However, the protection can be overcome if the cells are exposed to buffer with acidic pH (Sandvig and Olsnes, 1981). Under these conditions toxin bound at the cell surface penetrates directly through the surface membrane (Moskaug etal., 1988). 

When translocation is induced at the surface membrane, by exposure to low pH, only a fraction (10-50 %) of the bound toxin is translocated (Falnes et al., 1994 Moskaug ef al., 1987). A number of requirements... 

Humanity s major sources of energy are derived from fossil fuels, principally oil, gas, coal, and wood. The major combustion by-products of fossil fuel burning include sulfur dioxide (SO2), carbon dioxide (CO2), and nitric oxide (NO2), and partially oxidized hydrocarbons. The process of burning fossil fuels in thermal power plants, factories, homes, and motor vehicles emits enormous amounts of the aforementioned pollutants. The most important environmental concerns resulting from fossil fuel use are global climate change, acid rain, surface ozone, and partic-ulate-Zaerosol-bound toxins. 

Fig. 3. Binary delivery mechanism. Bispecific antibodies can be used to deliver the complementary parts of an effector molecule to two distinct target sites on the same cell. In the example shown one acid-triggered bispecific antibody carries the catalytic domain (C) of DT to a selected receptor whereas the second carries its transmembrane domain (T) to a different receptor site. Cooperation between these functional units should occur when both complexes enter the same endosome and their bound toxin domains are released by the low pH conditions. Greatly improved specificity results from targeting two distinct sites on the cell and unwanted side effects are reduced by using attenuated effector moieties whose activity is restored intracellularly.

The interaction of cholera toxin with vesicles is strong enough to permit perturbation in the lipid membrane, but it does not affect the dissociation of the active a-chain from the vesicle-bound toxin. 

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