Oxidative stress has long been linked to the pathogenesis of neurodegenerative diseases; however, whether it is a cause or merely a consequence of the degenerative process is still unknown. We show that mice deficient in Cu, Zn-superoxide dismutase (SOD1) have features typical of age-related macular degeneration in humans. Investigations of senescent Sod1 ؊/؊ mice of different ages showed that the older animals had drusen, thickened Bruch's membrane, and choroidal neovascularization. The number of drusen increased with age, and exposure of young Sod1 ؊/؊ mice to excess light induced drusen. The retinal pigment epithelial cells of Sod1 ؊/؊ mice showed oxidative damage, and their ␤-cateninmediated cellular integrity was disrupted, suggesting that oxidative stress may affect the junctional proteins necessary for the barrier integrity of the retinal pigment epithelium. These observations strongly suggest that oxidative stress may play a causative role in age-related retinal degeneration, and our findings provide evidence for the free radical theory of aging. In addition, these results demonstrate that the Sod1 ؊/؊ mouse is a valuable animal model to study human age-related macular degeneration.animal model ͉ superoxide dismutase A ge-related macular degeneration (AMD) is the leading cause of legal blindness in humans in developed countries (1-5). AMD is characterized by a progressive degeneration of the macula, usually bilateral, leading to a severe decrease in vision and a central scotoma. The decrease in vision results either from retinal degeneration, called geographic atrophy (dry or nonexudative AMD), or from the secondary effects of choroidal neovascularization (CNV; wet or exudative AMD). An early sign of AMD is the appearance of drusen, which are extracellular deposits that accumulate below the retinal pigment epithelium (RPE) and are known to be risk factors for developing CNV (6-8).Mouse models of AMD that manifest some of the features of human AMD have recently begun to appear (9-14); however, most of these mice have only some of the characteristics of human AMD (15). The severity of AMD in humans progresses with increasing age, finally resulting in extensive degeneration of the retina. Therefore, animal models that mimic the complex and progressive characteristics of AMD are needed to investigate the pathogenesis of AMD.Oxidative stress, which refers to cellular or molecular damage caused by reactive oxygen species (ROS), has been implicated in many age-related diseases and aging itself (16,17). ROS include free radicals, hydrogen peroxide, and singlet oxygen and are often the by-products of oxygen metabolism. The retina is particularly susceptible to oxidative stress because of its high consumption of oxygen, high concentration of polyunsaturated fatty acids, and exposure to light (18). A growing body of evidence suggests that cumulative oxidative damage may be responsible for AMD (18, 19); however, a causative link has not been definitively demonstrated (18).To determine whether there is a causative ro...

The interaction of clinically established anti‐inflammatory drugs with some proteins has shown these drugs to strongly inhibit heat coagulation of whole serum at a concentration attainable in the sera of patients. Phenylbutazone and sodium salicylate do not inhibit the biological activity of three biologically active and labile serum proteins, namely, necrotizing factor, heterogenous serum and complement. However, they do influence the effect of heat on these proteins. The relation between this drug action in vitro and the possible mode of action of the proteins in vivo is discussed.

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This study revealed that the ABC phenomenon is induced by PEG-modified PLA-nanoparticles. We consider that NP-L33s may be useful clinically for the sustained-release and targeted delivery of PGE(1).

The accelerated blood clearance (ABC) phenomenon is induced upon repeated injections of poly(ethylene glycol) (PEG)-coated colloidal carriers. It is essential to suppress this phenomenon in a clinical setting because the pharmacokinetics must be reproducible. In this study, we evaluated the induction of the ABC phenomenon using nanoparticles coated with various hydrophilic polymers instead of PEG. Nanoparticles encapsulating prostaglandin E1 were prepared by the solvent diffusion method from a blend of poly(lactic acid) (PLA) and block copolymers consisting of various hydrophilic polymers and PLA. Coating of nanoparticles with poly(N-vinyl-2-pyrrolidone) (PVP), poly(4-acryloylmorpholine), or poly(N,N-dimethylacrylamide) led to extended residence of the nanoparticles in blood circulation in rats, although they had a shorter half-life than the PEG-coated nanoparticles. The ABC phenomenon was not induced upon repeated injection of PVP-coated nanoparticles at various time intervals, dosages, or frequencies, whereas it was elicited by PEG-coated nanoparticles. In addition, anti-PVP IgM antibody, which is estimated to be one of the crucial factors for induction of the ABC phenomenon, was not produced after injection of PVP-coated nanoparticles. These results suggest that the use of PVP, instead of PEG, as a coating material for colloidal carriers can evade the ABC phenomenon.