A brief review is presented on observations leading to the current notions regarding neuro-inflammatory processes. The greatest focus is on Alzheimer's disease (AD) since this is where the most convincing data has been obtained. A brief summary of observations on the neuroprotective action of alpha-phenyl-tert-butyl-nitrone (PBN) as well as results of research designed to understand its mechanism of action is presented.
View Article and Find Full Text PDFOxidative DNA damage caused by a cysteine metal-catalyzed oxidation system (Cys-MCO) comprised of Fe(3+), O(2), and a cysteine as an electron donor was enhanced by copper, zinc superoxide dismutase (CuZnSOD) in a concentration-dependent manner, as reflected by the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) and strand breaks. Unlike CuZnSOD, manganese SOD (MnSOD) as well as iron SOD (FeSOD) did not enhance DNA damage. The capacity of CuZnSOD to enhance damage to DNA was inhibited by a spin-trapping agent, 5, 5-dimethyl-1-pyrroline N-oxide (DMPO) and a metal chelator, diethylenetriaminepentaacetic acid (DETAPAC).
View Article and Find Full Text PDFSleep deprivation is reported to have both beneficial and harmful effects upon host defenses. In the work reported herein, we address the effects of sleep deprivation on the mucosal anti-influenza defenses of both immune and nonimmune BALB/c mice. Sleep deprivation does not depress existing mucosal antiviral defenses in the respiratory tracts of BALB/c mice; in fact, it may actually be beneficial.
View Article and Find Full Text PDFOxidative stress has traditionally been viewed as a stochastic process of cell damage resulting from aerobic metabolism, and antioxidants have been viewed simply as free radical scavengers. Only recently has it been recognized that reactive oxygen species (ROS) are widely used as second messengers to propagate proinflammatory or growth-stimulatory signals. With this knowledge has come the corollary realization that oxidative stress and chronic inflammation are related, perhaps inseparable phenomena.
View Article and Find Full Text PDFBiochem Biophys Res Commun
July 2000
Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease believed to be caused by an inflammatory process in the pancreas leading to selective destruction of the beta cells. Inducible cyclooxygenase (COX-2) is expressed under inflammatory conditions and its product prostaglandin E(2) (PGE(2)) is an important inflammation mediator. We report here that administration of the selective COX-2 inhibitor NS-398 prevents the onset of diabetes in mice brought on by multiple low-doses of streptozotocin (STZ).
View Article and Find Full Text PDFThe mechanistic basis of the neuroprotective activity of the nitrone-based free radical trap PBN (alpha-phenyl-N-tert-butyl nitrone) has been investigated extensively. Key observations exclude its simple mass action spin trapping of free radicals activity as the key mechanism of action. These include: A) the fact that it protects in experimental stroke even if administered several hours after the event and B) the fact that its chronic low-level administration to old experimental animals reverses their age-enhanced susceptibility to stroke even several days after the last dosage.
View Article and Find Full Text PDFCytokines and nitric oxide (NO) have been implicated in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). We have shown that the spin-trapping agent phenyl N-tert-butylnitrone (PBN) protects against streptozotocin (STZ)-induced IDDM in mice. In order to gain more insights into the mechanism(s) of the protective action of PBN against IDDM, we have investigated the effect of this compound on the cytokine-induced NO generation (measured as nitrite) in rat insulinoma RIN-5F cells.
View Article and Find Full Text PDFRemoval of choline from the diet results in accumulation of triglycerides in the liver, and chronic dietary deficiency produces a non-genotoxic model of hepatocellular carcinoma. An early event in choline deficiency is the appearance of oxidized lipid, DNA and protein, suggesting that increased oxidative stress may facilitate neoplasia in the choline deficient liver. In this study, we find that mitochondria isolated from rats fed a choline-deficient, L-amino acid defined diet (CDAA) demonstrate impaired respiratory function, particularly in regard to complex I-linked (NADH-dependent) respiration.
View Article and Find Full Text PDFObjective: To examine knowledge, attitudes, current clinical practices, and educational needs of obstetrician-gynecologists regarding patients' alcohol use during pregnancy.
Methods: A 20-item, self-administered questionnaire on patients' prenatal alcohol use was sent to 1000 active ACOG fellows. Responses were analyzed using univariate and multivariate statistical techniques.
Nitric oxide (NO) is a lipophilic gaseous molecule synthesized by the enzymatic oxidation of L-arginine. During periods of inflammation, phagocytic cells generate copious quantities of NO and other reactive oxygen species. The combination of NO with other reactive oxygen species promotes nitration of ambient biomolecules, including protein tyrosine residues and membrane-localized gamma-tocopherol.
View Article and Find Full Text PDFThe p38 mitogen-activated protein kinase (p38-MAPK) is a central enzyme in one of the major protein kinase cascades that regulate proapoptotic and proinflammatory signal transduction. p38-MAPK is activated by receptor/ligand recognition events or by exposure to extracellular stressors, including oxidative stress. Activation of p38-MAPK is affected by dual phosphorylation on a specific inhibitory domain.
View Article and Find Full Text PDFContext: Rates of smoking are increasing among adolescents and young adults, but trends in smoking among pregnant women have not been studied.
Objective: To assess pregnancy-related variations in smoking behaviors and their determinants among women of childbearing age in the United States.
Design: Analysis of data collected between 1987-1996 from the Behavioral Risk Factor Surveillance System survey.
Multiple dose administration of methamphetamine (MA) results in long-lasting toxic effects in the nigrostriatal dopaminergic system. These effects are considered to be primarily due to oxidative damage mediated by increased production of hydrogen peroxide or other reactive oxygen species in the dopaminergic system. The present study was designed to determine the protective effects of dietary antioxidant selenium on MA-induced neurotoxicity in the nigrostriatal dopaminergic system.
View Article and Find Full Text PDFFree Radic Biol Med
December 1999
Unlabelled: Chronic hepatitis C virus (HCV) infection is associated with an increased production of reactive oxygen species within the liver that are responsible for the oxidation of intracellular macromolecules. To ascertain whether the increased risk of hepatocellular carcinoma in individuals with chronic HCV infection is related to an accumulation of oxidative DNA damage, the 8-hydroxydeoxyguanosine (8-OHdG) content in the DNA of liver tissue and leukocytes of 87 individuals with HCV- or HBV-related liver disease and of 10 healthy controls was measured. Serum levels of thiobarbituric acid reactive substances (TBARS) were also assessed as an index of lipid peroxidation.
View Article and Find Full Text PDFPhotochem Photobiol
December 1999
Methylene blue (MB) is being used as a sensitizer for the photodynamic inactivation of viral contaminants, including the human immunodeficiency virus, in blood and blood components used in medical treatment. We recently showed that oxygen-dependent photodynamic inactivation of the RNA bacteriophage Q beta with MB plus light (MB + L) is associated with the formation of 8-oxo-7,8-dihydroguanine, protein carbonyls, RNA-protein crosslinkages and minor amounts of RNA strand breaks. We report herein, with the use of infectious RNA assays, that the lethal lesions in Q beta phage following MB + L exposure can be accounted for, and thereby most likely reside in, the RNA component of the phage but that the protein component of the virion contributes to the inactivation.
View Article and Find Full Text PDFProc Soc Exp Biol Med
December 1999
Recently, clinical trials of several neurodegenerative diseases have increasingly targeted the evaluation of the effectiveness of various antioxidants. The results so far are encouraging but variable and thus confusing. Rationale for the possible clinical effectiveness of antioxidants in several degenerative conditions has arisen out of the many years of basic science generally showing that reactive oxygen species (ROS) and oxidative damage are important factors in the processes involved.
View Article and Find Full Text PDFNitrone-based free radical traps (NFTs) have been shown to be protective in several neurodegenerative models. Our research has strongly implicated that: A) several neurodegenerative conditions exhibit increased levels of pro-inflammatory cytokines which consequently result in increased levels of oxidative stress and B) that NFTs act in part by suppressing oxidative stress through suppression of the action of the cytokine cascade. Acquired Immune Deficiency Syndrome (AIDS) dementia complex (ADC) is one of several conditions where the data collected helped to develop these concepts.
View Article and Find Full Text PDFPreischemic hyperglycemia is known to aggravate brain damage resulting from transient ischemia. In the present study, we explored whether this aggravation is preceded by an enhanced formation of reactive oxygen species (ROS) during the early reperfusion period. To that end, normo- and hyperglycemic rats were subjected to 15 min of forebrain ischemia and allowed recovery periods of 5, 15, and 60 min.
View Article and Find Full Text PDFBackground: Frequent alcohol use during the first 8 weeks of pregnancy can result in spontaneous abortion and dysmorphologic changes in the developing organ systems of the embryo, including the heart, kidneys, and brain. However, few population-based studies are available that describe the prevalence of frequent drinking (6 or more drinks per week) among women prior to and during early pregnancy (the periconceptional period), and the sociodemographic and behavioral factors that characterize these women. Such knowledge is fundamental to the design of targeted interventions for the prevention of fetal alcohol syndrome (FAS) and other prenatal alcohol-related disorders.
View Article and Find Full Text PDFThe hypothesis, as stated in the title, has arisen from the failure of simpler notions to explain a series of otherwise difficult to understand observations and the mounting evidence, in a broader sense, that inflammatory processes in the CNS are important etiologically in neurodegenerative diseases. Novel aspects include the primacy of inflammatory processes, within the CNS, which leads to increased formation of "proinflammatory" cytokines that lead to increased formation of reactive oxygen species (ROS) and mediation of the upregulation of genes that produce toxic products such as reactive nitrogen species (RNS). Here I utilize important background reports and synthesize ideas to help account for the noted increases in ROS and RNS and their biological reaction products in neurodegenerative diseases.
View Article and Find Full Text PDFReversible protein phosphorylation regulates a wide array of cellular functions. Cells respond to cytokines and various stressors via phosphorylation and thus activation of one or more of the mitogen-activated protein kinase (MAPK) pathways. Involvement of these signal transduction pathways has been implicated in numerous pathologies, including inflammation.
View Article and Find Full Text PDFSystemic exposure to gram-negative bacterial substances such as lipopolysaccharide (LPS, or endotoxin) induces an uncontrolled, massive inflammatory reaction which culminates in multiple system organ failure and death. Septic shock often does not respond to corticosteroids; however, certain low-molecular-weight antioxidant compounds have been discovered to possess potent anti-inflammatory action, and some of these novel compounds can rescue animals from experimentally induced septic shock. Phenyl-N-tert-butylnitrone (PBN) is the archetype of the nitrone class of antioxidants which we have previously shown to suppress LPS-induced cytokine biosynthesis in vivo.
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