bluuebunny/crossref_metadata_2025 huggingface dataset:
Nonhuman Primate Model of the Effect of Prenatal Cocaine Exposure on Cerebral Cortical Development
Authors: LIDOW MICHAEL S.
Published: February 2006

ABSTRACT:To investigate the effects of prenatal cocaine exposure on the corticogenesis in primates we developed a monkey model in which pregnant animals received 10 mg/kg cocaine orally twice a day from the 40th to the 102nd day of pregnancy. The animals gave birth at term, and brains of the 2‐month and 1.5‐year‐old infants were examined. Examination revealed the structural abnormalities throughout the cerebral cortex that would be expected from modulation of the nonselectively diffusing circulation‐derived monoamines. They include: (1) reduction in the number of cortical cells, which most likely reflects abnormal cell proliferation; (2) inappropriate positioning of cortical neurons, which resulted from alterations in migration of cortical cells; and (3) altered glial morphology. The structural alterations were accompanied by abnormalities in animal temperament reminiscent of those seen in human infants of drug‐abusing mothers. As predicted by the morphologic studies, we found that cocaine treatment produced significant changes in the levels of monoamines and their receptors in all laminae of the frontal, parietal, temporal, and occipital regions of the fetal cerebral wall. This indicates that cocaine abuse by pregnant human mothers may affect the global levels of monoamines in the fetal brain and, in doing so, interfere with a broad range of developmental events regulated by these chemicals.
Prenatal Exposure to Cocaine Impairs Neuronal Coding of Attention and Discriminative Learninga
Authors: GABRIEL MICHAEL , TAYLOR CARRIE
Published: February 2006

ABSTRACT: Cingulate cortex and related areas of the thalamus are critically involved in the mediation of discriminative avoidance learning, wherein rabbits step in response to an acoustic conditional stimulus (CS+) to avoid foot shock and they learn to ignore a different acoustic stimulus (CS−) not followed by shock. Studies of multi‐unit neuronal activity recorded simultaneously in many cingulothalamic areas have documented massive learning‐related neuronal firing changes during the course of behavioral acquisition. Stimulated by findings (this volume) of neurobiological changes in anterior cingulate cortex in rabbits exposed in utero to cocaine, we investigated behavioral learning and correlated neuronal activity in several cingulothalamic areas in cocaine‐exposed rabbits. In an initial study, training‐induced enhancement of cingulate cortical neuronal firing in response to the CS+ and CS− was abolished in rabbits exposed to cocaine in utero. Yet discriminative neuronal activity (greater firing in response to the CS+ than to the CS−) did develop during training, and behavioral learning was normal in the cocaine‐exposed rabbits. In a second study, we reduced the salience of the CS+ and CS− by employing 200 msec CSs rather than standard 500 msec CSs. Early training‐stage development of anterior cingulate cortical discriminative neuronal activity was abolished, the elicited neuronal discharge profiles were altered, and behavioral learning was impaired in rabbits exposed to cocaine, relative to saline‐exposed controls. The specificity of these changes to low‐salience CSs suggested that prenatal cocaine results in disturbed associative attentional processes of anterior cingulate cortex in adult rabbits. Consideration of the neuronal response profile alterations together with other reported neurobiological changes suggested that the cocaine‐related attentional deficit is due to impaired dopaminergic afferent activation of GABA neurons in anterior cingulate cortex.
Neural Systems Underlying Arousal and Attention: Implications for Drug Abusea
Authors: ROBBINS T. W. , GRANON S. , MUIR J. L. , DURANTOU F. , HARRISON A. , EVERITT B. J.
Published: February 2006

ABSTRACT:The monoaminergic and cholinergic systems are implicated in different forms of behavioral arousal that can be dissected in terms of their forebrain targets and the nature of the behavioral processes they modulate in distinct regions. Thus, evidence in rats with selective neurochemical manipulations tested behaviorally using an analog of an attentional task developed for human subjects indicates that the coeruleo‐cortical noradrenergic system is implicated in divided and selective attention, the basal forebrain cholinergic system in stimulus detection, the mesostriatal and mesolimbic dopaminergic systems in response speed and vigor, and the mesencephalic serotoninergic or 5‐HT systems in response inhibition. Our recent studies have focused on fractionating, in the same task, the differential contributions of the dorsal and median raphé 5‐HT systems as well as elucidating the functions of the mesocortical dopaminergic system, each of which may be relevant to understanding the behavioral and cognitive sequelae of cocaine administration in human subjects as well as in experimental animals.
Prenatal Cocaine Exposure Alters Signal Transduction in the Brain D1 Dopamine Receptor Systema
Authors: FRIEDMAN EITAN , WANG HOAU‐YAN
Published: February 2006

ABSTRACT: Cocaine use during pregnancy may result in persistent behavioral abnormalities in the newborn. Animal studies show behavioral and neurochemical alterations in offspring that were exposed to cocaine prenatally. The monoamine neurons, including those containing dopamine, appear and become operational prenatally and mature during early postnatal life. It is therefore conceivable that exposure to cocaine during gestation may critically affect normal development and subsequently cause protracted postnatal neurochemical and behavioral changes. The data we obtained demonstrate that prenatal exposure to cocaine in the rabbit impairs signal transduction via the D1 but not the D2 dopamine receptor system. This is reflected in impaired dopamine‐stimulated [35S]GTPγS binding to Gαs without affecting binding of the nucleotide to Gαi in both cortex and striatum of rabbit offspring. This selective reduction in D1 dopamine receptor‐mediated activation of Gs protein increased in severity as the dose of cocaine administered to the pregnant dams was increased. Maximal impairment was observed after treatment with two daily injections of 3 mg/kg of cocaine HC1. The reduction in dopamine‐stimulated GTP binding to Gαs did not result from a decrease in concentration of membrane Gαs protein or D1 dopamine receptors. The data also indicate that in utero cocaine exposure causes persistent uncoupling of the D1 dopamine receptors from their associated Gs protein which appears as early as gestational day 22 and persists to postnatal day 100. The reduction in D1 dopamine receptor‐mediated signal transduction may be mediated by posttranslational modifications of the D1 dopamine receptor or of Gsα such as phosphorylation, which result in altered coupling between these membrane components. The resultant attenuated D1 dopamine receptor‐mediated signaling may ultimately underlie both long‐lasting behavioral dysfunction and morphologic changes which are associated with prenatal cocaine exposure in the rabbit.
A Mouse Model of Transplacental Cocaine Exposure: Clinical Implications for Exposed Infants and Childrena
Authors: KOSOFSKY BARRY E. , WILKINS AARON S.
Published: February 2006

ABSTRACT: To characterize the effects of cocaine on developing brain we have developed a mouse model of gestational cocaine exposure. We studied pregnant dams injected twice daily with cocaine HCl at 40, 20, or 10 mg/kg/day sc from embryonic days (E)8 to E17 (COC 40, COC20, and COC10, respectively), vehicle‐injected dams allowed access to food ad libitum (SAL) or pair‐fed with the COC 40 dams (SPF 40), animals pretreated with the short‐acting α‐adrenergic antagonist phentolamine prior to each cocaine injection (P COC 40), and animals administered phentolamine prior to saline (PHENT). COC 40, P COC 40, and SPF 40 dams demonstrated the lowest percentage weight gain during gestation. The surrogate‐fostered offspring of COC 40, P COC 40, and SPF 40 dams demonstrated transient brain and body growth retardation on postnatal days (P)1 and P9 when compared to pups born to SAL dams. We conducted behavioral tests which allowed us to dissociate the indirect effect of cocaine‐induced malnutrition from a direct effect of prenatal cocaine administration in altering postnatal behavior. Pups from all groups were tested for first‐order Pavlovian conditioning on P9 or P12 or for the ability to ignore redundant information in a blocking paradigm on P50. Unlike the SPF 40, PHENT, and SAL controls, COC 40 and P COC 40 mice were unable to acquire an aversion to an odor previously paired with shock on P9, a learning deficit that resolved by P12. However, on P50, COC 40 mice and, to a lesser extent, P COC 40 and SPF 40 mice demonstrated a persistent behavioral deficit in our blocking paradigm, which may reflect alterations in selective attention. We discuss how these findings in our rodent model have developmental implications for human infants exposed to cocaine in utero.
Prevention and Treatment Issues for Pregnant Cocaine‐Dependent Women and Their Infants
Authors: KALTENBACH KAROL , FINNEGAN LORETTA
Published: February 2006

ABSTRACT: The increase in cocaine use among pregnant women has created significant challenges for treatment providers. Drug‐dependent women tend to neglect general health and prenatal care. Perinatal management is often difficult due to medical, obstetrical, and psychiatric complications. Research has demonstrated that comprehensive care, including high risk obstetrical care, psychosocial services, and addiction treatment can reduce complications associated with perinatal substance abuse. Research investigating the effectiveness of residential and outpatient treatment for pregnant cocaine‐dependent women also suggests that many biopsychosocial characteristics and issues influence treatment outcomes. Homelessness and psychiatric illness require a more intensive level of care, and abstinence is difficult to maintain for many women in outpatient treatment as they continue to live in drug‐using environments. To optimize the benefit of comprehensive services, services should be provided within a multilevel model of substance abuse treatment including long‐ and short‐term residential, intensive outpatient, and outpatient settings.
Optimization and Chemical Control of Porphyrin‐Based Molecular Wires and Switches
Authors: HUSH NOEL S. , REIMERS JEFFREY R. , HALL LACHLAN E. , JOHNSTON LESLEY A. , CROSSLEY MAXWELL J.
Published: February 2006

ABSTRACT: The design rationale is described as are some experimental and theoretical developments concerning rigidly fused porphyrin molecular wires. These materials consist of porphyrin units fused to acene‐type bridges and have been synthesized in a range of topologies including linear porphyrin octamers of length ca. 120 Å. Next we demonstrate, for some linear oligoporphyrins, how the electronic coupling between the end porphyrin units can be modulated by simple (possibly in situ) chemical modulation of the bridging units. Specifically, the chemical systems considered involve either pH‐controlled protonation of bridge azines or conversion of bridge quinone or quinone dioxime rings to or from benzenoid or hydroquinone rings. In the most general terms, the electronic coupling through oligoporphyrin molecular wires is discussed in terms of a simple model in which complete end‐to‐end π electronic delocalization is required in order to provide strong long‐range interactions. Computationally, we monitor interorbital coupling using an appropriate mixture of density functional (B3LYP) and ab initio SCF computational schemes. Finally, we examine bridge modulation of the intermetallic coupling in three homovalent bis‐metallic oligoporphyrin systems, two in which Ru(CO)2 is complexed within terminal porphyrin rings, the other in which [Cu(I)Cl2]− is tethered using phenanthroline end groups. Results are obtained both using an effective two‐level model, appropriate for spectroscopic properties, and using a more general scheme, appropriate for molecular conduction.
Chemical Control of Tautomerization‐Based Molecular Electronic and Color Switches
Authors: REIMERS JEFFREY R. , HALL LACHLAN E. , HUSH NOEL S. , SILVERBROOK KIA
Published: February 2006

ABSTRACT: Many schemes which have been suggested for the chemical control of molecular electronic devices are impractical because of the large energy changes associated with bond breaking and reforming: these would result in unacceptably large amounts of energy being required for device operation. We have chosen to look in detail at a class of chemical reactions prominent in biological systems that, on energetic grounds, could produce a feasible device: tautomerization reactions of heterocyclic bases. In particular, we concentrate on a model reaction, the 4‐pyridinol/4(1H)‐pyridinone tautomerization, through which an aromatic pyridinol unit is converted into a π‐localized pyridinone unit. In these molecules the functionalities are arranged para, allowing the possibility that the molecules align in a solid phase in linear hydrogen‐bonded chains. The change in the π electronic structure associated with reactions of this type is quite large, as illustrated, for example, in the conversion of quinacridone, a brightly colored pigment, to quinacridol, an uncolored species with strong UV absorption. Our primary purpose is to calculate energy changes and reaction barrier heights to see whether such tautomerization reactions could provide the basis for an operational chemically controlled molecular electronic device. We also consider, briefly, other required properties in a practicable device.
Theory of Electrical Conduction Through a Molecule
Authors: EMBERLY ELDON G. , KIRCZENOW GEORGE
Published: February 2006

ABSTRACT: We present a theoretical study of electronic transport through a 1,4 benzene‐dithiolate (BDT) ion chemically bonded to two gold leads. The model consists of a single BDT attached to two Au clusters, which are in turn attached to ideal one‐dimensional leads. Extended Hückel theory is used to model the electronic structure and the Lippmann‐Schwinger equation is solved for the lead‐to‐lead transmission. The current‐voltage characteristics of the system are calculated using the finite temperature, finite voltage Landauer formula. Different atomic configurations of the Au clusters are examined including the effects of thermally induced positional disorder of the Au atoms. We find that while in some cases there is conduction via states derived from the BDT HOMO and LUMO levels, conduction due to levels derived from hybrid Au cluster‐BDT states often predominate. The current‐voltage characteristics are found to be sensitive to the specific configuration of the Au clusters, BDT and ideal leads.
Rectification by a Single Molecule of Hexadecylquinolinium Tricyanoquinodimethanide
Authors: METZGER ROBERT M. , CAVA MICHAEL P.
Published: February 2006

ABSTRACT: Asymmetries in the macroscopic and the nanoscopic direct‐current electrical conductivity through Langmuir‐Blodgett multilayers and monolayers of γ‐(n‐hexadecyl)quinolinum tricyanoquinodimethanide, HDQ‐3CNQ (1) can be ascribed to a transition from the ground‐state zwitterionic state (shown) to a presumably neutral excited‐state conformer, thus confirming indubitably rectification of electrical current by a single molecule.
Chemical Approaches of Molecular Switches
Authors: LAUNAY J. P. , COUDRET C.
Published: February 2006

ABSTRACT: Molecular switches are defined as molecules existing in two different states, an ON state, allowing a complete intramolecular electron transfer between two redox sites, and an OFF state, for which this transfer is blocked. The efficiency of electron transfer is measured by the Vab electronic coupling parameter, which can be obtained from intervalence transitions, and its various definitions are recalled. Then different switching mechanisms are reviewed: torsion, saturation/unsaturation of double bonds, and quantum interferences. Synthetic strategies such as creation of an unsaturation, condensation to generate a double bond, or connection of two conjugated systems to form a single bond, are discussed and put in perspective.
The Electrical Measurement of Molecular Junctions
Authors: REED M. A. , ZHOU C. , DESHPANDE M. R. , MULLER C. J. , BURGIN T. P. , JONES L. , TOUR J. M.
Published: February 2006

ABSTRACT: We present the investigation of the electrical transport of metal/(organic molecule or monolayer)/metal junctions. Utilizing a novel mechanically controllable break junction to form a statically stable system, we have self‐assembled molecules of benzene‐ 1,4‐dithiol onto two facing gold electrodes allowing for direct observation of charge transport through the molecules. Current‐voltage I(V) measurements provides a quantitative measure of the conductance of a junction containing a single molecule. We have also created a technique to form well‐defined, stable, and reproducible metallic contacts to a self‐assembled monolayer of 4‐thioacetylbiphenyl with nanoscale area. Electronic transport measurements show a prominent rectifying behavior arising from the asymmetry of the molecular heterostructure. Variable‐temperature measurements reveal the dominant transport mechanisms, such as thermionic emission for the Ti‐organic system. These techniques demonstrate the capability of electrically characterizing and engineering conductive molecular systems for future potential device applications.
Probing Electronic Properties of Conjugated and Saturated Molecules in Self‐Assembled Monolayers
Authors: WEISS P. S. , BUMM L. A. , DUNBAR T. D. , BURGIN T. P. , TOUR J. M. , ALLARA D. L.
Published: February 2006

ABSTRACT:We have measured the electron transport properties of single and bundled molecules imbedded in crystalline monolayers of alkanethiols self‐assembled on Au{111} surfaces. These measurements have been performed using scanning tunneling microscopy and microwave difference frequency alternating current scanning tunneling microscopy on molecules with saturated and fully conjugated chains. We have learned to separate the contributions of the molecules and of the tunneling junction. We have also found a means to determine the value of the contact conductance due to the choice of chemical connection to the substrate.
Molecular Landers
Authors: GOURDON ANDRÉ , TANG HAO
Published: February 2006

ABSTRACT: Molecular landers are molecules designed for the study of electron transport in a tip‐molecule‐surface experimental set‐up. They comprise a fully aromatic and rigid main board linked to several spacers (legs). When the molecular landers are adsorbed on a metallic surface, the spacers maintain the main board at such a distance from the surface that the aromatic part is electronically decoupled from the surface. One end of this board extends beyond the last spacer and can be chimisorbed by docking along a diatomic step. Therefore in this conformation, the current can flow between the STM tip at one position of the molecular board and the surface at the other end, and only through the aromatic part.
Scanning Tunneling Microscopy (STM) on Physisorbed Chemical Groups of Individual Immobilized Molecules
Authors: MANASSEN YISHAY , SHACHAL DOV
Published: February 2006

ABSTRACT: Most scanning tunneling microscopy (STM) studies of adsorbed molecules are performed either on molecules that are chemically bound to the surface or are part of a molecular monolayer. In the first case, the chemical reaction with the surface changes the surface local density of states. In the second one, the electrons tunnel through a physisorbed molecule. In the study described in this paper STM imaging is performed on isolated molecules immobilized on a clean semiconductor surface where atomic resolution is observed. This is an intermediate case.

The adsorption behavior of diene molecules on Si(111)7 × 7 was investigated. The molecules adsorb by reaction of the double bonds on the surface. In the reaction, the C=C bond is opened to create two neighboring Si‐C bonds. Two such C‐C bonds are used to immobilize the chain to the surface. The adsorption chemistry is affected not only by the nature of the Si‐C bond but also by steric limitations.

Performing STM imaging on such systems ensures that the position of the immobilized chemical group (in this case an aliphatic chain) could be clearly identified and that it was possible to image parts of the molecule that are not chemically bound to the surface. STM images of 1,13‐tetradecadiene revealed a white protrusion in the location of the aliphatic chain. The increase in transmission is explained by an additional channel for tunneling: through bond tunneling. Long‐range electron transfer through molecules is a widely known chemical and biochemical process. This observation opens the possibility to investigate this fundamental phenomenon in large details. The potential applications for molecular electronics are discussed.
Nanoscopic Molecular Memories
Authors: MATSUSHIGE K. , YAMADA H. , TADA H. , HORIUCHI T. , CHEN X. Q.
Published: February 2006

ABSTRACT: Scanning probe microscopy (SPM) was utilized to form novel nanometer‐scale memory units in organic molecular layers. One method is based on the conductivity changes induced in evaporated n‐paraffin films by imposing electric pulses. The scanning tunneling microscope (STM) image revealed clearly the formation of high‐conductive area, the spot size of which is as small as 1 nm, suggesting the creation of the extremely high‐density molecular memory over 1014 bit/cm2. Moreover, the analysis with the aid of a computer simulation demonstrated that the extraction of H atoms for n‐paraffin molecules by applying electric pulses results in the changes in the electric states as well as geometric conformation. Next, ferroelectric organic materials were utilized to construct another type of reversible molecular memory. Here, the nanometer‐scale polarization switching in ferroelectric (VDF/TrFE) films was achieved with the SPM technique by applying a positive or a negative electric voltage to the film spin‐coated on Pt substrate, and actually, several local domains with different polarities could be formed even within a small crystalite of about 200 nm in length. Finally, the possibility of creating the novel molecular memories of the next generation is discussed.
Electronic Interaction between Submonolayer Molecular Films and Substrates of Different Nature
Authors: WOLF H. C. , GÓMEZ U. , PORT H.
Published: February 2006

ABSTRACT: The electronic interaction between UHV‐deposited organic molecules (MePTCDI) and ultraclean insulating, semiconducting, and metal substrates (quartz, Ag, Si) is investigated. By means of submonolayer coverage (0.01 monolayer) intermolecular interaction is suppressed and quenching of molecular excitation is studied directly by analyzing the fluorescence lifetime as a function of the distance between molecule and substrate. The quenching on Ag(111) can quantitatively be described by the classical image dipole theory (CPS), implying interaction with the charge carriers in the metal. Quenching on the semiconductor Si(111) is much less effective and is explained by creation of electron/hole pairs in the substrate.
Evolution of Strategies for Self‐Assembly and Hookup of Molecule‐Based Devices
Authors: ALLARA D. L. , DUNBAR T. D. , WEISS P. S. , BUMM L. A. , CYGAN M. T. , TOUR J. M. , REINERTH W. A. , YAO Y. , KOZAKI M. , JONES L.
Published: February 2006

ABSTRACT: Strategies for self‐assembling molecule‐based devices are considered in terms of current chemical issues whose resolution appears critical to efficient connection and addressing of electronically active molecules between electrodes. We discuss issues related to the type and shape of the molecules, chemical bonding at junctions, molecular lengths and electrode gap matching, molecular alignment at electrodes, chemistry of deposited metal contacts, and the doping of molecular conductors. Examples of each of these aspects is given using fully conjugated molecules, constituted from rigid rod phenylene‐ethynylene units, self‐assembled onto metal and semiconductor surfaces.
Genes Involved in the Control of Cellular Proliferative Potentiala
Authors: REDDEL ROGER R.
Published: February 2006

ABSTRACT: Evidence that control of cellular proliferative potential may be linked to telomere length, along with data indicating that other factors may also be involved, will be reviewed. According to the telomere hypothesis of senescence, the sequential loss of telomeric repeat DNA that occurs during the replication of normal somatic cells eventually dictates the onset of the permanently nonreplicative state known as senescence. Many immortalized cells express telomerase, a ribonucleoprotein enzyme that replaces the telomeric DNA that would otherwise be lost due to replication. However, some immortalized human cells may avoid telomeric shortening without using telomerase. The mechanism involved is currently unknown, but other eukaryotes are able to replace telomeric DNA through (1) recombination and copy switching or (2) retrotransposition. Human fibroblasts that lose p53 function proliferate a limited number of times beyond the population‐doubling level at which their normal counterparts become senescent. Lack of functional retinoblastoma (Rb) protein (or equivalent events, such as loss of p16INK4 function, resulting in abrogation of Rb regulatory activity) also permits a temporary extension of proliferative potential. The p53 and pRb effects are additive, indicating that they exert their control on proliferative potential separately. The temporary life span extension associated with loss of p53 and/or Rb pathway function is accompanied by continued telomere shortening. The proliferation arrest that eventually ensues in p53‐minus cells or in p53‐minus/Rb‐minus cells may be regarded as terminal proliferation arrest states serving as a backup to senescence. p53‐minus/Rb‐minus cells cannot proliferate further unless they acquire the ability to prevent telomeric shortening. Somatic cell hybridization and microcell‐mediated chromosome transfer experiments indicate that immortalization involves the loss of function of other, as yet unidentified, genes; some of these may normally repress telomerase expression in somatic cells.
Chromosomal Damage Rate, Aging, and Dieta
Authors: FENECH MICHAEL
Published: February 2006

ABSTRACT: Chromosomal damage as measured by frequency of translocations, acentric fragments, telomere shortening, nondisjunction, chromosome loss, aneuploidy, and micronucleus formation has been shown to increase progressively with age. Using the cytokinesis‐block micronucleus technique, which provides an efficient measure of chromosomal breakage and loss, we have been able to show that aging can explain at least 25% of the variation in chromosomal damage rate in lymphocytes from both males and females. We have also performed cross‐sectional and placebo‐controlled intervention studies to determine the relationship between the micronucleus (MN) frequency in lymphocytes and diet, and blood status for vitamins C, E, B12, and folic acid. Our studies have shown that MN frequency in the 41‐ to 60‐year age group is significantly lower in vegetarians when compared to nonvegetarians, but the reverse was true in males aged between 20 and 40 years. This was accounted for by a deficient/low B12 status in vegetarian males; there was no difference in the MN frequency of vegetarian and nonvegetarian subjects aged between 61 and 90 years. Results from this study also showed significant negative correlations of MN frequency with folic acid and vitamin B12 but not with vitamin C or vitamin E. In separate studies on healthy men aged 50‐70, we have verified the significant negative correlation between vitamin B12 status in plasma and MN frequency (
r= 0.315

,
p = 0.013

) in subjects who were not vitamin B12 deficient and observed a significant positive correlation between MN frequency and homocysteine status (
r= 0.414

,
p = 0.0086

) in those men who were not vitamin B12 and/or folate deficient. These data suggest that MN frequency is minimized when plasma B12 is above 300 pmol/L and plasma homocysteine is below 7.5 μmol/L. Double‐blind placebo‐controlled intervention studies conducted over four months have shown that above RDI intake of vitamin E (30 × RDI) or folic acid (10 × RDI) did not produce a significant reduction in MN frequency in men aged 50‐70 years. In the latter case plasma homocysteine was reduced from a mean value of 9.33 μmol/L to 8.51 μmol/L, a level that does not correspond with minimization of MN frequency. We have also tested the hypothesis that moderate wine drinking can protect against the DNA‐damaging effect of hydrogen peroxide and found that there was a strong ex vivo inhibition (> 70%) of hydrogen peroxide‐induced MN frequency by plasma samples from blood collected one hour after consumption of red or white wine, as compared to plasma samples collected immediately before wine consumption (
p = 0.0008
). However, only samples following red wine consumption produced a significant reduction in baseline MN frequency. The above results suggest that chromosome damage can be modulated, under selected circumstances, by diverse dietary factors.
Pluripotent Protective Effects of Carnosine, a Naturally Occurring Dipeptidea
Authors: HIPKISS A. R. , PRESTON J. E. , HIMSWORTH D.T. M. , WORTHINGTON V. C. , KEOWN M. , MICHAELIS J. , LAWRENCE J. , MATEEN A. , ALLENDE L. , EAGLES P.A. M. , ABBOTT N. JOAN
Published: February 2006

ABSTRACT: Carnosine is a naturally occurring dipeptide (β‐alanyl‐l‐histidine) found in brain, innervated tissues, and the lens at concentrations up to 20 mM in humans. In 1994 it was shown that carnosine could delay senescence of cultured human fibroblasts. Evidence will be presented to suggest that carnosine, in addition to antioxidant and oxygen free‐radical scavenging activities, also reacts with deleterious aldehydes to protect susceptible macromolecules. Our studies show that, in vitro, carnosine inhibits nonenzymic glycosylation and cross‐linking of proteins induced by reactive aldehydes (aldose and ketose sugars, certain triose glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation product). Additionally we show that carnosine inhibits formation of MDA‐induced protein‐associated advanced glycosylation end products (AGEs) and formation of DNA‐protein cross‐links induced by acetaldehyde and formaldehyde. At the cellular level 20 mM carnosine protected cultured human fibroblasts and lymphocytes, CHO cells, and cultured rat brain endothelial cells against the toxic effects of formaldehyde, acetaldehyde and MDA, and AGEs formed by a lysine/deoxyribose mixture. Interestingly, carnosine protected cultured rat brain endothelial cells against amyloid peptide toxicity. We propose that carnosine (which is remarkably nontoxic) or related structures should be explored for possible intervention in pathologies that involve deleterious aldehydes, for example, secondary diabetic complications, inflammatory phenomena, alcoholic liver disease, and possibly Alzheimer's disease.
Intrinsic and Extrinsic Factors in Muscle Aging
Authors: CANNON JOSEPH G.
Published: February 2006

ABSTRACT: The regenerative potential of skeletal muscle, and overall muscle mass, decline with age. This regenerative potential may be influenced by autocrine growth factors intrinsic to the muscle itself. Extrinsic host factors that may influence muscle regeneration include hormones, growth factors secreted in a paracrine manner by accessory cells, innervation, and antioxidant mechanisms. Unaccustomed exercise, which involves mechanical overload of myofibers, provides a convenient method for studying muscle regeneration in both humans and animal models. An inflammatory response ensues in which distinctive populations of macrophages infiltrate the affected tissue: some of these macrophages are involved in phagocytosis of damaged fibers; other macrophages arriving at later times may deliver growth factors or cytokines that promote regeneration. These include fibroblast growth factor and insulin‐like growth factor, which are important regulators of muscle precursor cell growth and differentiation, as well as nerve growth factor, which is essential for maintenance or reestablishment of neuronal contact. Other cytokines, including interleukin‐1, tumor necrosis factor, interleukin‐15, and ciliary neurotrophic factor, have a strong influence on the balance between muscle protein synthesis and breakdown. The functional activity of invading macrophages can be influenced by age, by factors in myofibers and extracellular matrix, and can be influenced systemically by the antioxidant status of the host.
Age‐associated Changes in the Response of Skeletal Muscle Cells to Exercise and Regenerationa
Authors: GROUNDS MIRANDA D.
Published: February 2006

ABSTRACT: This paper looks at the effects of aging on the response of skeletal muscle to exercise from the perspective of the behavior of muscle precursor cells (widely termed satellite cells or myoblasts) and regeneration. The paper starts by outlining the ways in which skeletal muscle can respond to damage resulting from exercise or other trauma. The age‐related changes within skeletal muscle tissue and the host environment that may affect the proliferation and fusion of myoblasts in response to injury in old animals are explored. Finally, in vivo and in vitro data concerning the wide range of signaling molecules that stimulate satellite cells and other aspects of regeneration are discussed with respect to aging. Emphasis is placed on the important role of the host environment, inflammatory cells, growth factors and their receptors (particularly for FGF‐2), and the extracellular matrix.
Oxidative Stress and Aging: Role of Exercise and Its Influences on Antioxidant Systems
Authors: JI LI LI , LEEUWENBURGH CHRIS , LEICHTWEIS STEVE , GORE MITCH , FIEBIG RUSSEL , HOLLANDER JOHN , BEJMA JEFFERY
Published: February 2006

Strenuous exercise is characterized by an increased oxygen consumption and disturbance of intracellular prooxidant‐antioxidant homeostasis. At least three biochemical pathways, that is, mitochondrial electron transport chain, xanthine oxidase, and polymorphoneutrophil have been identified as potential sources of intracellular free radical generation during exercise. These deleterious reactive oxygen species pose a serious threat to the cellular antioxidant defense system, such as diminished reserve of antioxidant vitamins and glutathione, and have been shown to cause oxidative damage in exercising and/or exercised muscle and other tissues. However, enzymatic and nonenzymatic antioxidants have demonstrated great versatility and adaptability in response to acute and chronic exercise. The delicate balance between prooxidants and antioxidants during exercise may be altered with aging. Study of the complicated interaction between aging and exercise under the influence of reactive oxygen species would provide more definitive information as to how much aged individuals should be involved in physical activity and whether supplementation of nutritional antioxidants would be desirable.
Mitochondrial Aging: Open Questionsa
Authors: BECKMAN KENNETH B. , AMES BRUCE N.
Published: February 2006

ABSTRACT: Interest in the role of mitochondria in aging has intensified in recent years. This focus on mitochondria originated in part from the free radical theory of aging, which argues that oxidative damage plays a key role in degenerative senescence. Among the numerous mechanisms known to generate oxidants, leakage of the superoxide anion and hydrogen peroxide from the mitochondrial electron transport chain are of particular interest, due to the correlation between species‐specific metabolic rate (“rate of living”) and life span. Phenomenological studies of mitochondrial function long ago noted a decline in mitochondrial function with age, and on‐going research continues to add to this body of knowledge. The extranuclear somatic mutation theory of aging proposes that the accumulation of mutations in the mitochondrial genome may be responsible in part for the mitochondrial phenomenology of aging. Recent studies of mitochondrial DNA (mtDNA) deletions have shown that they increase with age in humans and other mammals. Currently, there exist numerous important and fundamental questions surrounding mitochondria and aging. Among these are (1) How important are mitochondrial oxidants in determining overall cellular oxidative stress? (2) What are the mechanisms of mitochondrial oxidant generation? (3) How are lesions and mutations in mtDNA formed? (4) How important are mtDNA lesions and mutations in causing mitochondrial dysfunction? (5) How are mitochondria regulated, and how does this regulation change during aging? (6) What are the dynamics of mitochondrial turnover? (7) What is the relationship between mitochondrial damage and lipofuscinogenesis? (8) What are the relationships among mitochondria, apopotosis, and aging? and (9) How can mitochondrial function (ATP generation and the establishment of a membrane potential) and dysfunction (oxidant generation) be modulated and degenerative senescence thereby treated?
Mitochondrial DNA Mutations and Age
Authors: OZAWA TAKAYUKI
Published: February 2006

ABSTRACT: Apopotic cell death is reported to be prominent in the stable tissues of the failing heart, in cardiomyopathies (CM), in the sinus node of complete heart block, in B cells of diabetes mellitus, and in neurodegenerative diseases. Recently, mitochondrial (mt) control of nuclear apoptosis was demonstrated in the cell‐free system. The mt bioenergetic crisis induced by exogenously added factors such as respiratory inhibitors leads to the collapse of mt transmembrane potential, to the opening of the inner membrane pore, to the release of the apoptotic protease activating factors into cytosol, and subsequently to nuclear DNA fragmentation. However, the endogenous factor for the mt bioenegertic crisis in naturally occurring cell death under the physiological conditions without vascular involvement has remained unknown. Recently devised, the total detection system for deletion demonstrates the extreme fragmentation of mtDNA in the cardiac myocytes of senescence, and mt CM harboring maternally inherited point mutations in mtDNA and on the cultured cell line with or without mtDNA disclosed that mtDNA is unexpectedly fragile to hydroxyl radial damage and hence to oxygen stress. The great majority of wild‐type mtDNA fragmented into over two hundreds types of deleted mtDNA related to oxidative damage, resulting in pleioplasmic defects in the mt energy transducing system. The mtDNA fragmentation to this level is demonstrated in cardiac myocytes of normal subjects over age 80, of an mtCM patient who died at age 20 and one who died at age 19, of a recipient of heart transplantation at age 7 with severe mtCM, and in mtDNA of a cultured cell line under hyperbaric oxygen stress for two days, leading a majority of cells to apoptotic death on the third day. The extreme fragility of mtDNA could be the missing link in the apoptosis cascade that is the physiological basis of aging and geriatrics of such stable tissues as nerve and muscle.
Tissue‐specific Distribution of Multiple Mitochondrial DNA Rearrangements during Human Aginga
Authors: KOVALENKO SERGEY A. , KOPSIDAS GEORGE , KELSO JOANNE , ROSENFELDT FRANKLIN , LINNANE ANTHONY W.
Published: February 2006

ABSTRACT: Mitochondria, according to the free radical theory of aging, are the major source of reactive oxygen species (ROS). The results, presented in this paper, question the role of reactive oxygen species in contributing significantly to the extent of mitochondrial bioenergy degradation of the tissues, which can be correlated with mtDNA rearrangements. We report here that mtDNA rearrangements, including deletions and duplications, in tissues from human aged subjects, occur in levels ranging from very low in liver, to considerable in cardiac muscle, to almost total in skeletal muscle. The extent of mtDNA rearrangements is correlated at both the individual tissue and cell level with cytochrome oxidase (COX) activity as the exemplifier of cellular bioenergy capacity. Thus, the ROS proposal in its simplest form as it affects mtDNA and mitochondrial electron transport system is not supported by the available data.
Influences of Caloric Restriction on Age‐associated Skeletal Muscle Fiber Characteristics and Mitochondrial Changes in Rats and Micea
Authors: LEE CONNIE M. , ASPNES LAUREN E. , CHUNG SUSAN S. , WEINDRUCH RICHARD , AIKEN JUDD M.
Published: February 2006

ABSTRACT: The effect of caloric restriction (CR) initiated in adult rats (17 months of age) on the abundance of deleted mitochondrial genomes, mitochondrial enzymatic abnormalities, and fiber number was examined in rat skeletal muscle. Vastus lateralis muscle from young (3‐4 months) ad libitum‐fed, old (30‐32 months) restricted (35% and 50% CR, designated CR35 and CR50, respectively), and old ad libitum‐fed rats (29 months) was studied. CR preserved fiber number and fiber‐type composition in the CR50 rats. In the old rats from all groups, individual fibers were found with either no detectable cytochrome‐c oxidase activity (COX−), hyperactive for succinate dehydrogenase activity (SDH++), or both COX− and SDH++. Muscle from the CR50 rats contained significantly fewer COX− and SDH++ fibers than did the muscle from the CR35 rats. CR50 rats also had significantly lower numbers of mtDNA deletion products in two (adductor longus and soleus) of the four muscles examined compared to CR35 rats. These data indicate that CR begun in late middle age can retard age‐associated fiber loss and fiber‐type changes as well as lower the number of skeletal muscle fibers exhibiting mitochondrial enzyme abnormalities. CR can also decrease the accumulation of deleted mitochondrial genomes.
The Universality of Bioenergetic Disease: Age‐associated Cellular Bioenergetic Degradation and Amelioration Therapy
Authors: LINNANE ANTHONY W. , KOVALENKO S. , GINGOLD E. B.
Published: February 2006

ABSTRACT: During the present century there has been a dramatic change in life expectancy in advanced societies, now exceeding 80 years. As distinct from life expectancy, life potential is said to be at least 120 years, so that the continuing increase in knowledge has the potential for further major changes in the survival of humans conceivably in the near future. This presentation will be concerned with one aspect of the development of biomedical advances related in part to a concept of an “age‐related universality of bioenergetic disease,” and its potential amelioration and proposed impact on age‐related disease and lifestyle. Aging is a complex biological process associated with a progressive decline in the physiological and biochemical performance of individual tissues and organs, leading to age‐associated disease and senescence. Consideration of the progressive accumulation of mitochondrial DNA mutation with age and the tissue/cellular bioenergy decline associated with the aging process has led us to the proposal of a “universality of bioenergetic disease” and the potential for a redox therapy for the condition. This concept envisages that a tissue‐bioenergetic decline will be intrinsic to various diseases of the aged and thereby contribute to their pathology, in particular, heart failure, degener ative brain disease, muscle and vascular diseases, as well as other syndromes. The information and concepts embodied in this proposal will be reviewed under the following headings: (1) mitochondrial DNA deletion mutation in some tissue is very extensive and shows mosaicism; (2) age‐associated tissue/cellular bioenergy mosaic closely corresponds to the mtDNA profile; (3) cellular bioenergy as a function of mitochondrial bioenergy, glycolysis, and plasma membrane oxidoreductase; (4) redox therapy for the reenergization of cells, tissues, and whole organs. A redox therapy based on coenzyme Q10 has demonstrated profound alteration in heart function of old rats; no significant effect was observed with young rats.
Immunohistochemical and ELISA Assays for Biomarkers of Oxidative Stress in Aging and Diseasea
Authors: ONORATO JOELLE M. , THORPE SUZANNE R. , BAYNES JOHN W.
Published: February 2006

ABSTRACT: Oxidative stress is apparent in pathology associated with aging and many age‐related, chronic diseases, including atherosclerosis, diabetes mellitus, rheumatoid arthritis, and neurodegenerative diseases. Although it cannot be measured directly in biological systems, several biomarkers have been identified that provide a measure of oxidative damage to biomolecules. These include amino acid oxidation products (methionine sulfoxide, ortho‐tyrosine (o‐tyr) and dityrosine, chlorotyrosine and nitrotyrosine), as well as chemical modifications of protein following carbohydrate or lipid oxidation, such as Nɛ‐(carboxymethyl)lysine and Nɛ‐(carboxyethyl)lysine, and malondialdehyde and 4‐hydroxynonenal adducts to amino acids. Other biomarkers include the amino acid cross‐link pentosidine, the imidazolone adducts formed by reaction of 3‐deoxyglucosone or methylglyoxal with arginine, and the imidazolium cross‐links formed by the reaction of glyoxal and methylglyoxal with lysine residues in protein. These compounds have been measured in short‐lived intracellular proteins, plasma proteins, long‐lived extracellular proteins, and in urine, making them valuable tools for monitoring tissue‐specific and systemic chemical and oxidative damage to proteins in biological systems. They are normally measured by sensitive high‐performance liquid chromatography or gas chromatography‐mass spectrometry methods, requiring both complex analytical instrumentation and derivatization procedures. However, sensitive immunohistochemical and ELISA assays are now available for many of these biomarkers. Immunochemical assays should facilitate studies on the role of oxidative stress in aging and chronic disease and simplify the evaluation of therapeutic approaches for limiting oxidative damage in tissues and treating pathologies associated with aging and disease. In this article we summarize recent data and conclusions based on immunohistochemical and ELISA assays, emphasizing the strengths and limitations of the techniques.