Multiple lines of evidence point to mitochondrial oxidative stress as a potential pathogenic cause for Parkinson's disease (PD). MitoQ is a powerful mitochondrial antioxidant. It is absorbed orally and concentrates within mitochondria where it has been shown to protect against oxidative damage. We enrolled 128 newly diagnosed untreated patients with PD in a double-blind study of two doses of MitoQ compared with placebo to explore the hypothesis that, over 12 months, MitoQ would slow the progression of PD as measured by clinical scores, particularly the Unified Parkinson Disease Rating Scale. We showed no difference between MitoQ and placebo on any measure of PD progression. MitoQ does not slow the progression of PD, and this finding should be taken into account when considering the oxidative stress hypothesis for the pathogenesis of PD.
Administration of the mitochondria-targeted anti-oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria-targeted anti-oxidants in HCV and other liver diseases are warranted.
Abstract-The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (Ͼ15ϫ) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.
Cardiac surgery using cardiopulmonary bypass (CPB) provokes a systemic inflammatory response. This is mainly triggered by contact activation of blood by artificial surfaces of the extracorporeal circuit. Although often remaining sub-clinical and resolving promptly at the end of CPB, in its most extreme form this inflammatory response may be associated with the development of the systemic inflammatory response syndrome (SIRS) that can often lead to major organ dysfunction (MODs) and death. Here, we review the pathophysiology behind the development of this "whole body" inflammatory response and some of the methods currently used to minimise it.
Magainin and PGLa are 23-and 21-residue peptides isolated from the skin of the African clawed frog Xenopus lueuis. They protect the frog from infection and exhibit a broad-spectrum antimicrobial activity in vitro. The mechanism of this activity involves the interaction of magainin with microbial membranes. We have measured the secondary structure and membrane-perturbing ability of these peptides to obtain information about this mechanism. Our results show that mgn2a forms a helix with an average length of less than 20 A upon binding to liposomes. At high concentrations (50 mg/mL) mgn2a spontaneously solubilizes phosphatidylcholine liposomes at temperatures above the gel-liquid-crystalline phase transition. Mgn2a appears to bind to the surface of liposomes made of negatively charged lipids without spontaneously penetrating the bilayer. Finally, mgn2a and PGLa interact together with liposomes in a synergistic way that enhances the helix content of one or both of the peptides and allows the peptides to more easily penetrate the bilayer. PGLa mixed with a small nonperturbing amount of magainin 2 amide is 25-43 times as potent as PGLa alone at inducing the release of carboxyfluorescein from liposomes. The results suggest that the mechanism of antimicrobial activity does not involve a channel formed by transmembrane helical peptides.M a g a i n i n , also known as PGSI (Giovannini et al., 1987; Terry et al., 1988), is a family of 23-residue peptides that are secreted from the skin of the African clawed frog. They protect the frog from wound infection and exhibit a broadspectrum antimicrobial activity in vitro (Zasloff, 1987;Zasloff et al., 1988). On a molar basis this activity is as potent as tetracycline against some organisms.PGLa, another antimicrobial peptide isolated from frog skin, has an antimicrobial activity that is comparable to that of magainin 2 (Soravia et al., 1988), but these peptides have little sequence homology. The sequences of magainin 1 amide (mgnla), magainin 2 amide (mgn2a), and PGLa are (Giovannini et al., 1987) mgn 1 a: Gly-He-GI y-Lys-Phe-Leu-His-Ser-Ala-Gly-LysPhe-Gly-Lys-Ala-Phe-Val-Gly-Glu-Ile-Met-Lys-Ser-NH2 mgn2a: Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-LysPhe-GI y-Lys-Ala-Phe-Val-GI y-Glu-He-Met-Asn-Ser-NH2 PGLa: Gly-Met-Ala-Ser-Lys-Ala-Gly-Ala-Ile-AlaGly-Lys-Ile-Ala-Lys-Val-Ala-Leu-Lys-Ala-Leu-NH2These peptides are positively charged and can form extremely amphiphilic helices about 30 A in length. These features are common to polypeptides that bind to and effect the permeability of lipid bilayers (Sparrow & Goto, 1982;DeGrado et al., 1981;Green et al., 1987), and it has been suggested that magainins might act as detergents or transmembrane helical channel formers (Zasloff, 1987;Guy & Raghunathan, 1988). Indeed, measurements using a single channel conductance apparatus indicate that magainin forms a voltage-dependent channel in artificial membranes (Cruciani et al., 1988). Magainin 2 amide causes membrane depolarization in Escherichia coli cells and cytochrome oxidase liposo...
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