Search PubMed⌕ Search

Biomedical subjects

Lester Packer

Publications and source records attributed to Lester Packer.

At least 19 recordsLinked to original sources
PubMed2006

Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid.

Chronic systemic exposure of mice, rats, and Drosophila to D-galactose causes the acceleration of senescence and has been used as an aging model. The underlying mechanism is yet unclear. To investigate the mechanisms of neurodegeneration in this model, we studied cognitive function, hippocampal neuronal apoptosis and neurogenesis, and peripheral oxidative stress biomarkers, and also the protective effects of the antioxidant R-alpha-lipoic acid. Chronic systemic exposure of D-galactose (100 mg/kg, s.c., 7 weeks) to mice induced a spatial memory deficit, an increase in cell karyopyknosis, apoptosis and caspase-3 protein levels in hippocampal neurons, a decrease in the number of new neurons in the subgranular zone in the dentate gyrus, a reduction of migration of neural progenitor cells, and an increase in death of newly formed neurons in granular cell layer. The D-galactose exposure also induced an increase in peripheral oxidative stress, including an increase in malondialdehyde, a decrease in total anti-oxidative capabilities (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities. A concomitant treatment with lipoic acid ameliorated cognitive dysfunction and neurodegeneration in the hippocampus, and also reduced peripheral oxidative damage by decreasing malondialdehyde and increasing T-AOC and T-SOD, without an effect on GSH-Px. These findings suggest that chronic D-galactose exposure induces neurodegeneration by enhancing caspase-mediated apoptosis and inhibiting neurogenesis and neuron migration, as well as increasing oxidative damage. In addition, D-galactose-induced toxicity in mice is a useful model for studying the mechanisms of neurodegeneration and neuroprotective drugs and agents.

Aging↗
PubMed2006

Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: protective effects of R-alpha-lipoic acid.

Chronic systemic exposure of D-galactose to mice, rats, and Drosophila causes the acceleration of senescence and has been used as an aging model. However, the underlying mechanism is as yet unclear. To investigate the mechanisms of neurodegeneration in this model, we studied cognitive function, hippocampal neuronal apoptosis and neurogenesis, and peripheral oxidative stress biomarkers and also the protective effects of the antioxidant R-alpha-lipoic acid. Chronic systemic exposure of mice to D-galactose (100 mg/kg, s.c., 7 weeks) induced a spatial memory deficit, an increase in cell karyopyknosis, apoptosis, and caspase-3 protein levels in hippocampal neurons, a decrease in the number of new neurons in the subgranular zone in the dentate gyrus, a reduction of migration of neural progenitor cells, and an increase in death of newly formed neurons in the granular cell layer. The D-galactose exposure also induced an increase in peripheral oxidative stress, including an increase in malondialdehyde and decreases in total antioxidative capabilities (T-AOC), total superoxide dismutase (T-SOD), and glutathione peroxidase (GSH-Px) activities. A concomitant treatment with lipoic acid ameliorated cognitive dysfunction and neurodegeneration in the hippocampus and also reduced peripheral oxidative damage by decreasing malondialdehyde and increasing T-AOC and T-SOD, without an effect on GSH-Px. These findings suggest that chronic D-galactose exposure induces neurodegeneration by enhancing caspase-mediated apoptosis and inhibiting neurogenesis and neuron migration, as well as increasing oxidative damage. In addition, D-galactose-induced toxicity in mice is a useful model for studying the mechanisms of neurodegeneration and neuroprotective drugs and agents.

Animals↗
PubMed2006

Intraindividual variability of plasma antioxidants, markers of oxidative stress, C-reactive protein, cotinine, and other biomarkers.

BACKGROUND: Within-person variability in biomarkers results in random error that can attenuate estimates of association. Little information on such variability is available for a number of nutrition-related biomarkers. METHODS: Blood samples obtained 2 to 4 weeks apart were analyzed for tocopherols, carotenoids, ascorbate, lipids, cotinine, C-reactive protein, and oxidative stress. Subjects (n = 206 men and women, mean age 45.4 years) were either smokers or passively exposed to smoke. We calculated intraindividual and interindividual variability and the number of measurements required to reduce attenuation. RESULTS: For most biomarkers, 2 measurements would be required to limit the attenuation of correlation coefficients to no lower than 90% of the true correlation. If only one measurement were obtained, observed correlations would be approximately 80-88% of true correlations. For regression coefficients, 3 or 4 measures would be required. Exceptions were ascorbic acid and malondialdehyde, for which a single measure resulted in little attenuation. CONCLUSIONS: For most serum markers, collection of 2 or more measurements per person is desirable to increase the ability to detect associations between biomarkers and health-related variables. If only one measure is possible, sample sizes should be planned to permit detection of associations that are likely to be observed, not the theoretical true associations. The results of this study, in which measurements were obtained 2 to 4 weeks apart, are relevant for epidemiologic research in which the exposure of interest is the subject's baseline or current status. It is likely that within-person variability would be greater over a period of months or years.

Adolescent↗
PubMed2005

Electron spin resonance assay of ascorbyl radical generation in mouse hippocampal slices during and after kainate-induced seizures.

As an index of oxidative status, we analyzed ascorbyl radical generation during and after kainate-induced seizures in mouse hippocampus, using an ESR spectrometer equipped with a special tissue-type quartz cell. A specific doublet ESR spectrum was observed after seizures, and the g value and the hyperfine coupling constant (hfcc) of the spectrum were identical with those of ascorbyl radical itself. Antiepileptic zonisamide inhibited the generation of ascorbyl radical accompanying the seizures.

Animals↗
PubMed2005

Effect of antioxidant-enriched diets on glutathione redox status in tissue homogenates and mitochondria of the senescence-accelerated mouse.

The main purpose of this study was to investigate whether consumption of diets enriched in antioxidants attenuates the level of oxidative stress in the senescence-accelerated mouse (SAM). In separate and independent studies, two different dietary mixtures, one enriched with vitamin E, vitamin C, L-carnitine, and lipoic acid (Diet I) and another diet including vitamins E and C and 13 additional ingredients containing micronutrients with bioflavonoids, polyphenols, and carotenoids (Diet II), were fed for 8 and 10 months, respectively. The amounts of glutathione (GSH) and glutathione disulfides (GSSG) and GSH:GSSG ratios were determined in plasma, tissue homogenates, and mitochondria isolated from five different tissues of SAM (P8) mice. Both diets had a reductive effect in plasma; however Diet I had relatively little effect on the glutathione redox status in tissue homogenates or mitochondria. Remarkably, Diet II caused a large increase in the amount of glutathione and a marked reductive shift in glutathione redox state in mitochondria. Overall, the effects of Diet II were tissue and gender specific. Results indicated that the glutathione redox state in mitochondria and tissues can be altered by supplemental intake of a relatively complex mixture of dietary antioxidants that contains substances known to induce phase 2 enzymes, glutathione, and antioxidant defenses. Whether corresponding attenuations occur in age-associated deleterious changes in physiological functions or life span remains unknown.

Aging↗
PubMed2005

Associations between apolipoprotein E genotype and circulating F2-isoprostane levels in humans.

Apolipoprotein E (apoE), an important determinant of plasma lipoprotein metabolism, has three common alleles (epsilon2, epsilon3, and epsilon4). Population studies have shown that the risk of diseases characterized by oxidative damage, such as coronary heart disease and Alzheimer's disease, is significantly higher in epsilon4 carriers. We evaluated the association between apoE genotypes and plasma F2-isoprostane levels, an index of lipid peroxidation, in humans. Two hundred seventy-four healthy subjects (104 males, 170 females; 46.9 +/- 13.0 yr; 200 whites, 74 blacks; 81 nonsmokers, 64 passive smokers, and 129 active smokers) recruited for a randomized clinical antioxidant intervention trial were included in this analysis. ApoE genotype was determined by PCR and restriction enzyme digestion. Free plasma F2-isoprostane was measured by GC-MS. Genotype groups were compared using multiple regression analysis with adjustment for sex, age, race, smoking status, body mass index, plasma ascorbic acid, and beta-carotene. Subjects with epsilon3/epsilon4 and epsilon4/epsilon4 genotype (epsilon4-carriers) and with epsilon2/epsilon3 and epsilon3/epsilon3 (non-epsilon4-carriers) were pooled for analysis. In subjects with high cholesterol levels (total cholesterol above 200 mg/dl), plasma F2-isoprostane levels were 29% higher in epsilon4 carriers than in non-epsilon4-carriers (P= 0.0056). High-cholesterol subjects that are epsilon4 carriers have significantly higher levels of lipid peroxidation as assessed by circulating F2-isoprostane levels.

Apolipoproteins E↗
PubMed2005

Proceedings from the "Third International Conference on Mechanism of Action of Nutraceuticals".

The "Third International Conference on Mechanisms of Action of Nutraceuticals" (ICMAN 3) was held to bring investigators from around the world together to find answers and share experience relevant to the role of nutraceuticals in health and disease. Dietary supplements are currently receiving recognition as being beneficial in coronary heart disease, cancer, osteoporosis and other chronic and degenerative diseases such as diabetes, Parkinson's and Alzheimer's diseases. This gave impetus to investigate the mechanisms of action of nutraceuticals and related bioactive compounds in disease pathologies. Many lines of evidence indicate that the mechanistic actions of natural compounds involve a wide array of biological processes, including activation of antioxidant defenses, signal transduction pathways, cell survival-associated gene expression, cell proliferation and differentiation and preservation of mitochondrial integrity. Furthermore, many of these compounds exert anti-inflammatory actions through inhibition of oxidative stress-induced transcription factors (e.g., NF-kappaB, AP-1), cytotoxic cytokines and cyclooxygenase-2. It appears that these properties play a crucial role in the protection against the pathologies of numerous age-related or chronic diseases. This review summarizes the latest research finding in functional foods and micronutrients in the promotion of health and reduction of risk for major chronic diseases as presented in this symposium.

Antioxidants↗
PubMed2005

Vitamins E and C are safe across a broad range of intakes.

A robust database shows that dietary supplements of vitamins E and C are safe for the general population. Because these nutrients supply antioxidant and other functions for homeostasis and protection against free radical damage, supplementation has been intensively studied. Because of perceived benefits, many persons consume quantities of vitamins E and C well above the recommended dietary allowances. As safety guidance, tolerable upper intake levels have been established by the Food and Nutrition Board, Institute of Medicine, at 1000 mg for vitamin E and 2000 mg for vitamin C in adults. Many clinical trials with these vitamins have involved subjects with various diseases, and no consistent pattern of adverse effects has occurred at any intake. Numerous studies of vitamin C supplementation have provided no pattern of evidence to support concerns about safety other than occasional gastrointestinal upset or mild diarrhea resulting from the osmotic effects of unabsorbed quantities of vitamin C. Evidence of bleeding effects and other potential adverse effects of high vitamin E intakes in humans is not convincing. Evidence of adverse effects of vitamin C that result from its effects on iron absorption and metabolism has not been confirmed in clinical trials. Thus, we conclude from clinical trial evidence that vitamin E supplements appear safe for most adults in amounts </=1600 IU (1073 mg RRR-alpha-tocopherol or the molar equivalent of its esters) and that vitamin C supplements of </=2000 mg/d are safe for most adults.

Antioxidants↗
PubMed2004

In vivo ozone exposure induces antioxidant/stress-related responses in murine lung and skin.

Lung and skin are the organs directly exposed to environmental pollution. Ozone (O(3)) is a toxic, oxidant air pollutant, and exposure has been shown to induce antioxidant depletion as well as oxidation of lipids and proteins within the outermost skin layer (stratum corneum) and the lung respiratory tract lining fluids (RTLFs). To further define skin and lung responses to O(3) exposure, SKH-1 hairless mice were exposed to either 0.8 ppm of O(3) (a level occasionally reached in very polluted areas) or ambient air 6 h/day for 6 consecutive days. O(3) exposure resulted in the depletion of alpha-tocopherol in lung and plasma and induction in both skin and lung of heme oxygenase 1, cyclooxygenase 2, and proliferating cell nuclear antigen. O(3)-exposed animals showed a similar extent of upregulation of COX-2 and PCNA in lung and skin, whereas HO-1 was more responsive in skin than in lung (7-fold induction vs. 2-fold induction). In addition to these measures of response to oxidative stress, O(3) exposure led to the activation of nuclear factor kappaB measured as IkappaBalpha phosphorylation in both tissues. We conclude that in this model, O(3) at high pollutant levels is able to affect both lung and skin biology, inducing depletion of alpha-tocopherol and inducing stress-related responses in both skin epidermis and respiratory tract epithelium.

Air Pollution↗
PubMed2004

Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation.

OBJECTIVE: C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers. DESIGN: Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements. SETTING: Berkeley and Oakland, California. SUBJECTS: Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (> or =10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis. INTERVENTIONS: Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg alpha-tocopherol, 171 mg gamma-tocopherol, 252 mg mixed tocotrienols, and 95 mg alpha-lipoic acid). MEASURES OF OUTCOME: Change in plasma CRP concentration. RESULTS: Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to -5.5%, p = 0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations. CONCLUSIONS: Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.

Antioxidants↗
PubMed2004

Alpha-tocopherol transfer protein deficiency in mice causes multi-organ deregulation of gene networks and behavioral deficits with age.

Functions of alpha-tocopherol (alpha-T) in vivo, other than those for fertility in females, are intensely debated. The discovery of alpha-T deficiency in patients with ataxia (AVED) followed by the identification of mutations in the gene encoding alpha-tocopherol transfer protein (TTP) in AVED patients demonstrates an essential role of alpha-T and TTP for normal neurological function. alpha-T molecular targets that account for alpha-T-sensitive neurological dysfunction remain to be discovered. We have used high-density oligonucleotide arrays to search for putative alpha-T-sensitive genes in the CNS and other tissues in an in vivo model of alpha-T deficiency imposed at birth by the deletion of the TTP gene in mice. Repression of genes affecting synaptic function and myelination and induction of genes for neurodegeneration in the motor cortex of alpha-T-deficient mice were identified. The expression of retinoic acid-related orphan receptor alpha (ROR-alpha) was repressed in the cortex and adrenal glands of TTP-deficient mice. Deficiency of ROR-alpha causes ataxia in mice and may account for ataxia in AVED patients. These observations suggest that some of the actions of alpha-T are mediated by the transcription factor ROR-alpha. The behavior of young TTP-null mice was essentially normal, but older mice showed inactivity, ataxia, and memory dysfunction. mRNA profiles of old alpha-T-deficient cerebral cortices are compatible with repressed activity of oligodendrocytes and astrocytes. In conclusion, gene-expression profiling studies have identified novel alpha-T-modulated genes and cells in the CNS that may be causatively linked with delayed neurodegeneration and age-related decline in behavioral repertoires.

Aging↗
PubMed2003

Gene expression profile of oxidant stress and neurodegeneration in transgenic mice deficient in alpha-tocopherol transfer protein.

Alpha-tocopherol transfer protein (TTP) regulates the retention and secretion of alpha-tocopherol (alpha-T) by the liver. Deletion of the TTP gene (Ttpa) in mice results in systemic deficiency of alpha-T and neurological dysfunctions described in patients with mutated Ttpa. We have explored genome-wide changes in mRNAs from brain cortex and liver of Ttpa-deficient (Ttpa(-/-)) mice and wild-type (Ttpa(+/+)) mice. Selective inductions of genes regulated by antioxidant response elements were detected in Ttpa(-/-) livers compared to Ttpa(+/+) livers, suggesting increased oxidant stress in Ttpa(-/-) livers. The activation of cell proliferation pathways in Ttpa(-/-) livers was indicated by the induction of genes that encode growth factor-binding proteins, mitogen-activated protein kinase kinase 3, and apoptosis inhibitor 6. The induction of synuclein-alpha and repression of synuclein-beta genes was detected in Ttpa(-/-) cortex. This may predispose Ttpa(-/-) cortex to increased formation of synuclein-alpha aggregates and Lewy body, often associated with oxidant stress. Cortex of Ttpa(-/-) mice revealed repression of genes encoding synaptic proteins, protein kinase C family members, and myelin proteins. A 13-fold decrease in the expression of retinoic acid receptor-related orphan receptor-alpha mRNA predicts staggerer-like phenotype (ataxia and deficits of motor coordination) of Ttpa(-/-) mice. The repression of specific genes that determine synaptic plasticity and neuronal development may account for suppressed electrophysiological activities of cortex and impaired behavior in Ttpa(-/-) mice.

Animals↗
PubMed2003

Alpha-lipoic acid decreases thiol reactivity of the insulin receptor and protein tyrosine phosphatase 1B in 3T3-L1 adipocytes.

Alpha-lipoic acid is known to increase insulin sensitivity in vivo and to stimulate glucose uptake into adipose and muscle cells in vitro. In this study, alpha-lipoic acid was demonstrated to stimulate the autophosphorylation of insulin receptor and glucose uptake into 3T3-L1 adipocytes by reducing the thiol reactivity of intracellular proteins. To elucidate mechanism of this effect, role of protein thiol groups and H(2)O(2) in insulin receptor autophosphorylation and glucose uptake was investigated in 3T3-L1 adipocytes following stimulation with alpha-lipoic acid. Alpha-lipoic acid or insulin treatment of adipocytes increased intracellular level of oxidants, decreased thiol reactivity of the insulin receptor beta-subunit, increased tyrosine phosphorylation of the insulin receptor, and enhanced glucose uptake. Alpha-lipoic acid or insulin-stimulated glucose uptake was inhibited (i) by alkylation of intracellular, but not extracellular, thiol groups downstream of insulin receptor activation, and (ii) by diphenylene iodonium at the level of the insulin receptor autophosphorylation. alpha-Lipoic acid also inhibited protein tyrosine phosphatase activity and decreased thiol reactivity of protein tyrosine phosphatase 1B. These findings indicate that oxidants produced by alpha-lipoic acid or insulin are involved in activation of insulin receptor and in inactivation of protein tyrosine phosphatases, which eventually result in elevated glucose uptake into 3T3-L1 adipocytes.

3T3 Cells↗
PubMed2003

Alpha-lipoic acid inhibits adipocyte differentiation by regulating pro-adipogenic transcription factors via mitogen-activated protein kinase pathways.

Obesity is associated with a number of pathological disorders such as non-insulin-dependent diabetes, hypertension, hyperlipidemia, and cardiovascular diseases. alpha-Lipoic acid (LA) has been demonstrated to activate the insulin signaling pathway and to exert insulin-like actions in adipose and muscle cells. Based on this similarity LA is expected to promote adipogenesis in pre-adipocytes. Here, however, we report that LA inhibited differentiation of 3T3-L1 pre-adipocytes induced by a hormonal mixture or troglitazone. Northern blot analysis of cells demonstrated that this inhibition was accompanied with attenuated expression of adipocyte-specific fatty acid-binding protein and lipoprotein lipase. Electrophoretic mobility shift assay and Western blot analysis of cells demonstrated that LA modulates transcriptional activity and/or expression of a set of anti- or pro-adipogenic transcription factors. LA treatment of 3T3-L1 pre-adipocytes also resulted in prolonged activation of major mitogen-activated protein kinase signaling pathways but showed little or no effect on the activity of the insulin receptor/Akt signaling pathway. These findings suggest that LA inhibits insulin or the hormonal mixture-induced differentiation of 3T3-L1 pre-adipocytes by modulating activity and/or expression of pro- or anti-adipogenic transcription factors mainly through activating the MAPK pathways.

3T3 Cells↗