Evidence obtained over the past two decades shows that reactive oxygen species (ROS) are involved in brain lesions, including those due to cerebral ischemia-reperfusion. The mitochondria are the primary intracellular source of ROS, as they generate huge numbers of oxidative-reduction reactions and use massive amounts of oxygen. When anoxia is followed promptly by reperfusion, the resulting increase in oxygen supply leads to overproduction of ROS. In ischemic tissues, numerous studies have established a direct role for ROS in oxidative damage to lipids, proteins, and nucleic acids. Thus, mitochondria are both the initiator and the first target of oxidative stress. Mitochondrial damage can lead to cell death, given the role for mitochondria in energy metabolism and calcium homeostasis, as well as the ability of mitochondria to release pro-apoptotic factors such as cytochrome C and apoptosis-inducing factor (AIF). This review discusses possible mitochondrion-targeted strategies for preventing ROS-induced injury during reperfusion. The sequence of events that follow oxidative damage provides the outline for the review: thus, we will discuss protection of oxidative phosphorylation, mitochondrial membrane integrity and fluidity, and antioxidant or mild-uncoupling strategies for diminishing ROS production. Among mechanisms of action, we will describe the modulation of mitochondrial permeability transition pore (MPTP) opening, which may not only operate as a physiological Ca(2+) release mechanism, but also contribute to mitochondrial deenergization, release of pro-apoptotic proteins, and protection by ischemic preconditioning (IPC). Finally, we will review genetic strategies for controlling apoptotic protein expression, stimulating mitochondrial oxidative defences, and increasing mitochondrial proliferation.

The binding of docetaxel to human plasma proteins was studied by ultrafiltration at 37 degrees C and pH 7.4. Docetaxel was extensively (> 98%) plasma protein bound. At clinically relevant concentrations (1-5 micrograms/ml), the plasma binding was concentration-independent. Lipoproteins, alpha1-acid glycoprotein and albumin were the main carriers of docetaxel in plasma, and owing to the high interindividual variability of alpha1-acid glycoprotein plasma concentration, particularly in cancer, it was concluded that alpha1-acid glycoprotein should be the main determinant of docetaxel plasma binding variability. Drugs potentially coadministered with docetaxel (cisplatin, dexamethasone, doxorubicin, etoposide, vinblastine) did not modify the plasma binding of docetaxel. In blood, docetaxel was found to be mainly located in the plasma compartment (less than 15% associated to erythrocytes).

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Background: Heparan sulfates (HS) are important cell behavior regulators. Results: With age, HS structural changes affect myocardial growth factor functionalities. Conclusion: This reveals the importance of HS on the control of essential tissue repair effectors during aging. Significance: Changes in cardiac HS may alter tissue homeostasis and impair heart function. This might also limit the success of protein therapies and implantation of therapeutic cells.

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The importance of mitochondria is rising as a target in pathologic processes such as ischemia. We have investigated the effects of hydrocortisone, prednisolone, dexamethasone and triamcinolone on oxidative phosphorylation, Ca 2+ fluxes, swelling and membrane potentials in isolated kidney mitochondria. The measurement of respiration state 3 showed a significant decrease in presence of glucocorticoids whereas the other respiration states were not modified. When mitochondria were uncoupled and either the complexes III and IV or the complex IV were stimulated, the O P consumption was decreased by glucocorticoids. These results suggest the cytochrome c oxidase is a target of the glucocorticoid effect on the respiratory chain. Indeed, the other mitochondrial functions investigated were unchanged, ruling out a direct effect on Ca 2+ fluxes or swelling. A regulation of cytochrome c oxidase activity by glucocorticoids will be of particular interest in pathology involving metabolic insult.z 1998 Federation of European Biochemical Societies.

A number of neurodegenerative diseases, as Parkinson, prion, and Alzheimer's diseases, has been directly associated with altered conformations of certain peptides or proteins that assemble to form highly organized aggregates, also called amyloid fibers. Glycosaminoglycans have shown to play important roles on fibrils formation, stability and resistance to proteolysis. This manuscript reviews from basic concepts on the biochemistry and biology of glycosaminoglycans to their implications in neurodegeneration with particular emphasis in pathologic protein aggregation. Prion protein, Aβ42, Tau, and α-synuclein, are all proteins that can interact with glycosaminoglycans. We document here how these interactions may modify protein conformation, aggregation kinetics, and fibers stabilization with important consequences in disease. We also raise questions which answers may make advance the understanding of the implication of GAGs in neurodegeneration.