Membrane perturbations

Weltzem, H.U. (1979). Cytolytic and membrane-perturbing properties of lysophosphatidylcholine. Biochim. Biophys. Acta 559, 259-287. 

C NMR. The membrane perturbation by PRC H+ is found to be relatively smaller than DBC H. The ring current effect on the EPC h NMR signal is not substantial at any site. Only significant NMR downfield shift is noticed in the carbonyl site, as shown in Fig. 10. The difference in the perturbation effect between DBC H and PRC H supports the difference in the trapped site in bilayers and that in the anesthetic mechanism between the two drugs. 

Before the first indication of the existence of cannabinoid receptors, the prevailing theory on the mechanism of cannabinoid activity was that cannabinoids exert their effects by nonspecific interactions with cell membrane lipids (Makriyannis, 1990). Such interactions can increase the membrane fluidity, perturb the lipid bilayer and concomitantly alter the function of membrane-associated proteins (Loh, 1980). A plethora of experimental evidence suggests that cannabinoids interact with membrane lipids and modify the properties of membranes. However, the relevance of these phenomena to biological activities is still only, at best, correlative. An important conundrum associated with the membrane theories of cannabinoid activity is uncertainty over whether cannabinoids can achieve in vivo membrane concentrations comparable to the relatively high concentrations used in in vitro biophysical studies (Makriyannis, 1995). It may be possible that local high concentrations are attainable under certain physiological circumstances, and, if so, some of the cannabinoid activities may indeed be mediated through membrane perturbation. 

Other systems like electroporation have no lipids that might help in membrane sealing or fusion for direct transfer of the nucleic acid across membranes they have to generate transient pores, a process where efficiency is usually directly correlated with membrane destruction and cytotoxicity. Alternatively, like for the majority of polymer-based polyplexes, cellular uptake proceeds by clathrin- or caveolin-dependent and related endocytic pathways [152-156]. The polyplexes end up inside endosomes, and the membrane disruption happens in intracellular vesicles. It is noteworthy that several observed uptake processes may not be functional in delivery of bioactive material. Subsequent intracellular obstacles may render a specific pathway into a dead end [151, 154, 156]. With time, endosomal vesicles become slightly acidic (pH 5-6) and finally fuse with and mature into lysosomes. Therefore, polyplexes have to escape into the cytosol to avoid the nucleic acid-degrading lysosomal environment, and to deliver the therapeutic nucleic acid to the active site. Either the carrier polymer or a conjugated endosomolytic domain has to mediate this process [157], which involves local lipid membrane perturbation. Such a lipid membrane interaction could be a toxic event if occurring at the cell surface or mitochondrial membrane. Thus, polymers that show an endosome-specific membrane activity are favorable. 

While ionophore-stimulated 5-LO product release from neutrophils is often used as an indication of 5-LO inhibition, one must interpret these results cautiously. For example, halothane, an inhalation anaesthetic which may cause membrane perturbation [26], and colchicine, a microtubule disrupter [27], both were active, but presumably not because of 5-LO inhibition. A23187 is assumed to stimulate 5-LO by raising the intracellular calcium level, but this agent causes many other effects which may or may not be related to 5-LO activation, including changes in membrane potential, protein phosphorylation, phospholipid turnover, cyclic nucleotide levels, and DNA and protein synthesis [28]. Also, the effects of some putative 5-LO inhibitors on product release from neutrophils has been shown to vary with the stimulant used [29]. 

S. Jean-Louis, S. Akare, M. A. Ali, E. A. Mash, E. Meuillet and J. D. Martinez, Deoxycholic acid induces intra-cellular signalling through membrane perturbation, J. Biol. Chem., 2006, 281, 14948. 

Yu et al. (1998) were able to increase tha/itno antifungal efLciency of amphotericin B while at the same time decreasing its hemolytic activity by loading the drug into polymeric micelles. It was suggested that polymeric micelles could stabilize amphotericin B against autooxidation and/or enhance membrane perturbation of fungal cells. 

Mui, B., Ahkong, Q., Chow, L. and Hope, M. (2000) Membrane perturbation and the mechanism of lipid-mediated transfer of DNA into cells. Biochim. Biophys. Acta, 1467, 281-292. 

Other enhancing mechanisms have been proposed. Tomita et al. [153] reported that NaCIO enhances permeability through the transcellular route through membrane perturbation [153]. Similarly, Kajii et al. [92] demonstrated that NaSA caused a significant decrease... 

A, Inhibition of proteolytic enzymes B, dissociation of hexameric to monomeric form of insulin C, loosening of tight junctions D, increase in membrane fluidity due to cholesterol removal E, reversible ciliostasis F, mucoadhesion and prolonged residence time G, incorporation into lipid bilayer and membrane perturbation H, insulin internalization, increased transcellular transport and I, correlation with CMC. 

Loosening of tight junctions as well as membrane perturbation... 

In the absence of Ca2+e, a-LTX only binds to LPH1 and PTPc. Ca2+-independent exocytosis requires the presence of Mg2+ and toxin insertion into the plasma membrane, but these conditions also induce formation of a-LTX channels. Influx of Na+ and efflux of K+ through these channels and associated efflux of small molecules and influx/efflux of water may cause secretion. In addition, transmitter release can be caused by membrane perturbation or direct interaction with secretory machinery. Some secretion may be nonvesicular. Receptor-mediated signaling can cause the activation of PKC in some cells. However, Ca2+-independent release is blocked by La3+, indicating that toxin pores play a crucial role in this release. 

Typically, at these concentrations some membrane damage was found and in some cases it was widespread. Following exposure to 1.0 to 1.5 ug/ml nonylphenol, more than 20% of the cells manifested an unusual ultrastructural deformation of their flagellae indicative of microtubular damage, Figure 4a and b. Similar effects were also observed when C. angulosa was exposed to naphthalene or crude oil (34, 35). Membrane perturbations of this type has been related to their lipophilia, as they are sorbed, so the membranes expand thereby impairing their function (8). 

This question of direct interaction with nerve proteins or indirect interaction via membrane perturbation has also been tackled by ESR spectroscopy. Two types of labeling have been used fatty acids for lipid labeling and maleimide for frog nerve proteins. The anesthetics used were halothane as an example of a general anesthetic and procaine, lidocaine, and tetracaine as examples of local anesthetics. The latter interact primarily with head groups but can also merge into the hydrophobic hydrocarbon... 

Magzoub, M., L.E.G. Eriksson, and A. Graslund (2003) Comparison of the interaction, positioning, structure induction and membrane perturbation of cell-penetrating peptides and non-translocating variants with phospholipid vesicles. Biophys. Chem. 103, 271-288. 

Murakami, M., Kambe, T., Shimbara, S., Higashino, K., Hanasaki, K., Arita, H., Horiguchi, M., Arita, M., Arai, H., Inoue, K. and Kudo, I., 1999, Different functional aspects ofthe group II subfamily (Types IIA and V) and type X secretory phospholipase A(2)s in regulating arachidonic add release and prostaglandin generation. Implications of cyclooxygenase-2 induction and phospholipid scramblase-mediated cellular membrane perturbation../. Biol. Chem., 274 31435-31444. 

Tables II and III list equations which resulted from the present data bank from the following query list all equations linear in log P where activity is defined as log 1/C having intercepts <1 and having at least five data points per set. Study of this print-out yielded the conclusion (9) that the equations of this type now in hand fell into two major classes those of Table II with slopes of mean and standard deviation of 1.07 =t. 14 and those of Table III with slopes of 0.74 = =. 09. The equations were divided into the two sets solely on the basis of slope without regard to the kind of biological action involved. It would seem that all of the biological processes of Table II might be brought about by membrane perturbation. Comparison of the equations of Table II with the following average equation (10) for hemolysis lends credence to this hypothesis ...

The mean slope for the 17 examples of Table II is 1.07 . 14. The equations have been ordered with respect to intercept with an overall difference in this parameter of about 1 log unit. Thus, narcosis of tadpoles requires about one-tenth lower concentration of drug than the 50% inhibition of indophenol oxidase (Equation 3). The equation most nearly resembling the model equation (Equation 18) is Equation 6 correlating the structure-activity relationship between the concentration of ROH necessary to produce a 5-mv change in the rest potential of the lobster axon. This close relationship between hemolysis and nerve membrane perturbation has been noted by others using different techniques (II, 12). The relationships of Table II show that different sets of molecules acting on very different systems can be compared quickly in numerical terms. 

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