Lester Packer

University of Southern California | USC · Department of Pharmacology and Pharmaceutical Sciences

Insulin resistance is an important feature of type 2 diabetes (T2D) and obesity. The underlying mechanisms of insulin resistance are still unclear. Mitochondrial dysfunction, including mitochondrial loss and over-production of oxidants, has shown to be involved in the development of insulin resistance and Β-cell dysfunction [1,2]. In prediabetic an...

Metabolic dysfunction due to loss of mitochondria plays an important role in diabetes, and stimulation of mitochondrial biogenesis by anti-diabetic drugs improves mitochondrial function. In a search for potent stimulators of mitochondrial biogenesis, we examined the effects and mechanisms of lipoamide and α-lipoic acid (LA) in adipocytes. Different...

The role of R-α-lipoic acid as a cofactor (lipoyllysine) in mitochondrial energy metabolism is well established. Lipoic acid non-covalently bound and exogenously administered to cells or supplemented in the diet is a potent modulator of the cell's redox status. The diversity of beneficial effects of lipoic acid in a variety of tissues can be mechan...

Male C57BL/6 mice were fed diets supplemented with either β-carotene (BC) or lycopene (LY) that were formulated for human consumption. Four weeks of dietary supplementations results in plasma and lung carotenoid (CAR) concentrations that approximated the levels detected in humans. Bioactivity of the CARs was determined by assaying their effects on...

Mitochondrial dysfunction due to oxidative stress and concomitant impaired beta-cell function may play a key role in type 2 diabetes. Preventing and/or ameliorating oxidative mitochondrial dysfunction with mitochondria-specific nutrients may have preventive or therapeutic potential. In the present study, the oxidative mechanism of mitochondrial dys...

alpha-Lipoic acid (LA) has been widely studied as an agent for preventing and treating various diseases associated with oxidative disruption of mitochondrial functions. To investigate a related mitochondrial antioxidant, we compared the effects of lipoamide (LM), the neutral amide of LA, with LA for measures of oxidative damage and mitochondrial dy...

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In human cells, α-lipoic acid (LA) is present in a bound lipoyllysine form in mitochondrial proteins that play a central role in oxidative metabolism. The possible effects of oral LA supplementation, a single bout of strenuous exercise and endurance exercise training on the lipoyllysine content in skeletal muscle and liver tissues of rat were exami...

Abstract— The precise molecular description of the time dependent steps in the uptake, translocation and release of protons by bacteriorhodopsin following photon absorption requires information on the time resolved changes in protonation of the side chains of specific amino acid residues and the correlation of these changes with photocycle kinetics...

Aims/hypothesis: The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-alpha-lipoic acid (LA) and acetyl-L-carnitine (ALC), as well...

D-galactose (D-gal) -induced aging models in Drosophila, houseflies, mice and rats have been widely used; however, the underlying mechanisms are poorly understood. To investigate the involvement of mitochondrial dysfunction of D-gal, mitochondrial function was examined in the brain and liver of C57BL/6J mice, subjected to a treatment of D-gal with...

Nitroxide spin labels have been used successfully for a diversity of biological studies. Recently another application of spin labels has evolved - the measurement of bioenergetic parameters. These bioenergetic parameters are: cell volumes, pH and electrical gradients across membranes, electrical surface and boundary potentials, and one-electron red...

Vitamin E deficiency in rats increased the sensitivity of liver and muscle mitochondria to damage during incubation at various temperatures, irradiation with visible light, or steady-state respiration with substrates. In all cases, vitamin E-deficient mitochondria exhibited increased lipid peroxidation, reduced transmembrane potential, decreased re...

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. Blood samples obtained 2 to 4 weeks apart were analyzed for tocopherols, carotenoids, ascorbate, lipids, cotinine, C-reactive protein, and oxid...

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 ox...

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 we...

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 die...

Vitamin E (VE) is a potent lipid soluble antioxidant that prevents the propagation of free-radical damage in biological membranes. Tocopherols and tocotrienols are part of an interlinking set of antioxidant cycles, which has been termed the antioxidant network. Besides its antioxidant properties, cell regulatory activities of VE have been found. Ad...

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...

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...

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...

Alpha-tocopherol transfer protein (alpha-TTP) is a liver cytosolic transport protein responsible for maintenance of plasma alpha-tocopherol (alpha-T) concentrations. Symptoms of vitamin E deficiency, including neurological disorders such as ataxia, in alpha-TTP-deficient (TTP-/-) mice can be attenuated if dietary alpha-T is sufficiently augmented....

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. Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to s...

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 sk...

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 o...

Lycopene has repeatedly been shown to inhibit the growth of human prostate cells in vitro. However, previous studies with lycopene have focused on cancer specimens, and it is still unclear whether this carotenoid affects the growth of normal human prostate cells as well. Therefore, we investigated the effects of lycopene on normal human prostate ep...

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...

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...

Ozone (O(3)) is among the most reactive environmental oxidant pollutants to which cutaneous tissues are exposed. O(3) exposure has been shown to induce antioxidant depletion as well as the oxidation of lipids and proteins within the outermost skin layer, the stratum corneum. However, relatively little is known regarding the potential effects of O(3...

Exposure to environmental tobacco smoke (ETS) has been linked to increased risk of lung cancer and cardiovascular diseases in nonsmokers. Current research suggests that some of these diseases are associated with elevated oxidative stress. We investigated the effect of antioxidant (AO) intervention on the lipid peroxidation biomarker F2-isoprostanes...

Benzoyl peroxide (BPO) is a commonly used drug in the treatment of acne vulgaris, but it induces unwanted side effects related to stratum corneum (SC) function. Since it has been recently shown to oxidize SC antioxidants, it was hypothesized that antioxidant supplementation may mitigate the BPO-induced SC changes. To test this, 11 subjects were sel...

Free radicals in cigarette smoke may cause oxidative damage to macromolecules, contributing to cardiovascular diseases and cancer. Decreased plasma antioxidant concentrations may indicate cigarette smoke-related oxidative stress. We compared the effects on plasma antioxidant concentrations in cotinine-confirmed active and passive smokers with those...

The decoding of the human genome has completely changed our views on medicine. Beyond sequencing, tools of the postgenomic era may lead to a better understanding of various therapies, especially those with a complex effect on numerous cellular components and functions. The development of high-density oligonucleotide microarrays led to pioneer studi...

Clinical and pre-clinical uses of Ginkgo biloba extract encompass a broad spectrum of pathologies that include peripheral arterial disorders, cardiovascular and neuronal dysfunctions and resolution of ischemia-reperfusion injuries. Many of these pathologies develop over time and recruit multiple cell types and molecular pathways that alter the cell...

Ozone (O(3)) is among the most reactive environmental oxidant to which skin is exposed. O(3) exposure has previously been shown to induce antioxidant depletion as well as lipid and protein oxidation in the outermost skin layer, the stratum corneum (SC), but little is known regarding the potential effects of O(3) on the skin epidermis and dermis. To...

Isoflavonoids are thought to be the biologically active components in soy that play a role in the prevention of coronary heart disease and breast and prostate cancer. Mechanisms to explain how isoflavonoids mediate beneficial effects have not yet been clearly established. This study was undertaken to investigate the free radical-scavenging and anti...

As the outermost barrier of the body, the skin is directly and frequently exposed to a prooxidative environment, including solar UVA and UVB radiation, and air pollution. The skin is equipped with an elaborate system of antioxidant substances and enzymes that includes a network of redox active antioxidants. Among these, vitamin E has been identifie...

Oxidation of biomolecules may play a role in susceptibility to a number of diseases. However, there are few large-scale survey data describing oxidative damage that occurs in humans and the demographic, physical, or nutritional factors that may be associated with it. Such information is essential for the design and analysis of studies investigating...

Reactive oxygen (ROS) and nitrogen oxide (RNOS) species are produced as by-products of oxidative metabolism. A major function for ROS and RNOS is immunological host defense. Recent evidence indicate that ROS and RNOS may also function as signaling molecules. However, high levels of ROS and RNOS have been considered to potentially damage cellular ma...

The effect of plant flavonoids on intercellular adhesion molecule-1 (ICAM-1) expression in human keratinocyte was investigated. ICAM-1 is known to mediate skin inflammation. Among the flavonoids tested, taxifolin was the most potent in inhibiting interferon gamma (IFN gamma)-induced ICAM-1 protein as well as mRNA expression in human keratinocytes....

Reactive oxygen and nitrogen metabolites are obligatory and essential products of metabolism. Unregulated increase in their production is associated with a number of chronic illnesses. Diets rich in fruits, vegetables, and wines are implicated in the prevention of chronic diseases. Molecular mechanisms by which fruits and vegetables confer their di...

This study was performed to investigate the free radical scavenging activity of Panax red ginseng C.A. Meyer aqueous extract on 1,1-dipheny-2-picrylhydrazyl (DPPH), carbon-centered radical, hydroxyl and superoxide radicals using Electron Spin Resonance (ESR) spectrometer and spin-trapping techniques. Two different Red ginseng aqueous extracts prepa...

Free radicals in cigarette smoke (CS) cause oxidative damage to proteins, DNA, and lipids, contributing to the pathobiology of atherosclerosis, heart disease, and cancer. In vitro studies have shown that antioxidants quench free radicals and ameliorate certain aspects of biomolecular damage caused by CS. It is hypothesized that a combination of ant...

Antioxidant activities of freeze-dried preparations of a 70% acetone extract of pomegranate (Punica granatum L.) and its three major anthocyanidins (delphinidin, cyanidin, and pelargonidin) were evaluated. Free radical scavenging activities were examined using an ESR technique with spin trapping; DMPO for hydroxyl (.OH) and superoxide (O(2)(.-) ) r...

The insulin signaling pathway has been reported to mediate R-alpha-lipoic acid- (R-LA-)-stimulated glucose uptake into 3T3-L1 adipocytes and L6 myotubes. We investigated the role of the thiol antioxidant dihydrolipoic acid (DHLA) and intracellular glutathione (GSH) in R-LA-stimulated glucose transport and explored the hypothesis that R-LA could inc...

Currently available kwowledge on 1)the presence and physiological distribution of natural antioxidants in skin 2)their response to oxidative environmental stressors 3)the photoprotective potential of topically applied antioxidants.

A standardized herbal extract, containing flavonoids and terpenoids, from leaves of Ginkgo biloba trees is used as a dietary supplement for the prevention and treatment of a broad spectrum of human diseases (McKenna et al., 2001). Recently, its use as a remedy for age related decline in neurological functions has become more popular (DeFeudis and D...

Water-dispersible beadlets of carotenoids were used as supplements for human umbilical vein endothelial cells (HUVECs), human peripheral blood mononuclear cells (PBMCs) and human monocytes. Stability, cellular association and cytotoxicity of the carotenoid beadlets were compared with carotenoids delivered with tetrahydrofuran (THF). Incubations wit...

Benzoyl peroxide (BP) is used as a topical treatment for acne. Besides its anti-bacterial activity, the exact molecular mechanisms underlying its mode of action are not fully understood. In the current study, the effects of BP on cell viability, antioxidant status and, IL-1 and IL-8 gene expression were investigated in HaCaT keratinocytes. Keratino...

To examine the molecular events associated with selenium (Se) and vitamin E (VE) deficiency, we applied cDNA array technology to define the transcriptional response in the liver of Se- and VE-deficient rats. VE deficiency alone did not induce any significant changes in expression profile among the genes evaluated. Se deficiency lead to a down-regul...

Extracts of Ginkgo biloba leaves are consumed as dietary supplements to counteract chronic, age-related neurological disorders. We have applied high-density oligonucleotide microarrays to define the transcriptional effects in the cortex and hippocampus of mice whose diets were supplemented with the herbal extract. Gene expression analysis focused o...

In the present study, the effects of 4-hydroxy-2-nonenal (HNE) on highly purified pyruvate dehydrogenase complex (PDC) and its catalytic components in vitro and on PDC, α-ketoglutarate dehydrogenase complex (KGDC), and the branched-chain α-keto acid dehydrogenase complex (BCKDC) activities in cultured human HepG2 cells were investigated. Among the...

The aim of this study was to investigate the effect of the mitochondrial cofactor α-lipoic acid [R (+) LA] or its lipoamide analogue, 2-(N,N-dimethylamine) ethylamido lipoate [R (+) LA-plus], on nitric oxide (NO) production in RAW 264.7 macrophages. NO production from RAW 264.7 cells stimulated with 10 μg/mL of lipopolysaccharide and 50 U/mL of int...

The procyanidin-rich French maritime pine bark extract Pycnogenol (PBE) has been investigated for its effect in protecting human skin against solar UV-simulated light-induced erythema. Twenty-one volunteers were given an oral supplementation of Pycnogenol: 1.10 mg/kg body weight (b. wt.)/d for the first 4 weeks and 1.66 mg/kg b. wt./d for the next...

Although lipid peroxidation in the subendothelial space has been hypothesized to play a central role in atherogenesis, the role of vitamin E in preventing lipid peroxidation and lesion development remains uncertain. Here we show that in atherosclerosis-susceptible apolipoprotein E knockout mice, vitamin E deficiency caused by disruption of the α-to...

Currently, bioflavonoids have been known to have strong antioxidant capacities, and a variety of efforts have been made to identify the utilities of bioflavonoids in treating various diseases based on their antioxidant capacities. The effects of bioflavonoids extracted from the bark of Pinus maritima Pycnogenol (PYC) on free radical formation, acti...

Pycnogenol, an extract from French maritime pine bark (PBE), is a complex mixture of bioflavonoids with reported protective effects against disease. PBE is an effective scavenger of reactive oxygen species, and its main constituents are procyanidins of various chain lengths. To find out the biochemical basis of action of on enzyme activity, involve...

In the redox antioxidant network, dihydrolipoate can synergistically enhance the ascorbate-dependent recycling of vitamin E. Since the major endogenous thiol antioxidant in biological systems is glutathione (GSH) it was of interest to compare the effects of dihydrolipoate with GSH on ascorbate-dependent recycling of the water-soluble homologue of v...

In the redox antioxidant network, dihydrolipoate can synergistically enhance the ascorbate-dependent recycling of vitamin E. Since the major endogenous thiol antioxidant in biological systems is glutathione (GSH) it was of interest to compare the effects of dihydrolipoate with GSH on ascorbate-dependent recycling of the water-soluble homologue of v...

Macrophage inducible nitric oxide synthase is able to generate massive amounts of nitric oxide (NO) which contributes to the host immune defense against viruses and bacteria. Monocyte-macrophages stimulated with the bacterial wall component lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFN-γ) express the inducible form of nitric oxid...

Flavonoids are potent antioxidants and have been associated with lowering the risk of cardiovascular diseases. In this study, the effect of flavonoids (monomers, dimers and a trimer) as well as French maritime pine bark extract, Pycnogenol, on NO production, tumor necrosis factor-alpha (TNF-alpha) secretion and nuclear factor (NF)-kappaB activity w...

Expression of intercellular adhesion molecule-1 (ICAM-1) is necessary for leukocyte/keratinocyte interactions. Upregulation of ICAM-1 expression in keratinocytes has been observed in several inflammatory dermatoses, such as psoriasis, atopic dermatitis, and lupus erythematosus. Inflammatory cytokines, such as interferon-γ (IFN-γ), upregulate ICAM-1...

There is increasing evidence that thiols play a role in various biological processes. This arises from their ability to undergo redox reactions; thus, they can act as efficient electron donators or acceptors. α-Lipoic acid is a dithiol-containing compound that plays an essential role in mitochondrial dehydrogenase reactions, but it has recently gai...

This chapter describes a sensitive tape stripping-based technique to noninvasively obtain stratum corneum (SC) samples from human subjects, and an extraction and high-performance liquid chromatography (HPLC) analysis procedure to measure α-tocopherol and cholesterol in SC samples. This technique allows measurement of these compounds in consecutivel...

This chapter describes a quantitative assay procedure based on the use of radioisotope-labeled arginine for nitric oxide synthase inductive NOS (iNOS) enzyme activity, and summarizes the efficacy of either various purified flavonoids or the folk herbal medicines, Ginkgo biloba extract and Pinus rnarittima proprietary extract. iNOS—which tightly bin...

Publisher Summary Naturally occurring lipoic acid is known to play a fundamental role in metabolism, serving as a cofactor in enzyme complexes, which function at strategic points in carbohydrate metabolism, citric-acid cycle, and amino-acid catabolism. In the last decade, experimental evidence has increased suggesting free lipoic acid to be a power...

α-Lipoic acid, also known as thioctic acid, 1,2-dithiolane-3-pentanoic acid, 1,2-dithiolane-3-valeric, or 6,8-thioctic acid, is a naturally occurring potent antioxidant. It is present as lipoyllysine in various natural sources. In the plant material studied, the lipoyllysine content was the highest in spinach (3.15 μg/g dry weight; 92.51 μg/mg prot...

Publisher Summary Uyaku (in Japanese, Wu Yao in Chinese, Oyak in Korean) is the dried roots of L. strychnifolia E Villar of the Lauraceae family, and a traditional Asian medicine used in China as an astringent, carminative, stomachic, or tonic for asthma, cholera, congestion, dyspepsia, dysmenorrhea, fluxes, gonorrhea, hernia, malaria, menorrhagia,...

EGb 761 has been shown to directly scavenge many of the reactive oxygen and nitrogen species, such as nitric oxide, hydroxyl, superoxide, and peroxyl radicals. Some of the protective effects of EGB 761 may thus be attributed to its direct radical scavenging activity. Regulatory effects of EGb 761 on two major cellular systems, nitric oxide metaboli...

Despite accumulating data on the beneficial effects of bionormalizer (BN), the biological mechanisms responsible for the therapeutic activity of BN are not well understood. This chapter evaluates its activity under various conditions to gain further insights into the biological mechanisms of BN action and new possibilities for therapeutic applicati...

Skin plays an important part in the protection against oxidative stressors, such as ultraviolet radiation, ozone, and chemicals. This study was based on the observation that upper facial stratum corneum contained significantly higher levels of the antioxidant alpha-tocopherol than corresponding layers of arm stratum corneum. We hypothesized that th...

In vitro studies have shown that α-lipoic acid (LA) is an antioxidant. There is a paucity of studies on LA supplementation in humans. Therefore, the aim of this study was to assess the effect of oral supplementation with LA alone and in combination with α-tocopherol (AT) on measures of oxidative stress. A total of 31 healthy adults were supplemente...

Herbal extracts with antioxidant properties are enjoying increasing popularity as remedies for acute and chronic illnesses such as depression, memory loss, cardiovascular disorders and immunological deficiencies. The molecular targets of these complex mixtures of botanical extracts are poorly understood. We have evaluated a well-characterised herba...

Elevated levels of extracellular glutamate have been linked to reactive oxygen species mediated neuronal damage and brain disorders. Lipoic acid is a potent antioxidant that has previously been shown to exhibit neuroprotection in clinical studies. A new positively charged water soluble lipoic acid amide analog, 2-(N,N-dimethylamine) ethylamido lipo...

Radical scavenging by reconstituted lyophilized powders of water extracts from 16 common vegetables was measured using electron spin resonance (ESR) with 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), hydroxyl radicals, (·OH) or superoxide anion radicals (02·-), as DMPO-OH or DMPO-OOH spin adducts. On a dry weight basis, eggplant, and red, yellow and gre...

To examine the stereospecific effects of lipoic compounds on pyruvate metabolism, the effects of R-lipoic acid (R-LA), S-lipoic acid (S-LA) and 1,2-diselenolane-3-pentanoic acid (Se-LA) on the activities of the mammalian pyruvate dehydrogenase complex (PDC) and its catalytic components were investigated. Both S-LA and R-LA markedly inhibited PDC ac...

This chapter discusses the determination of oxidized and reduced lipoic acid using high-performance liquid chromatography (HPLC) and coulometric detection. α-lipoic acid has generated considerable clinical interest as a cellular thiol-replenishing and redox-modulating agent. Biologically, lipoate (LA) exists as lipoamide in at least five proteins w...

Lipophilic antioxidants are responsible for the protection of cell membranes against lipid peroxidation. Vitamin E is the major lipophilic antioxidant in plasma, membranes, and tissues and is the collective name for the eight naturally occurring molecules (four tocopherols and four tocotrienols) that exhibit α-tocopherol activity. This chapter disc...