6 results on '"Hamdheydari L"'
Search Results
2. The arachidonic acid 5-lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor alpha activation of microglia and extends survival of G93A-SOD1 transgenic mice.
- Author
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West M, Mhatre M, Ceballos A, Floyd RA, Grammas P, Gabbita SP, Hamdheydari L, Mai T, Mou S, Pye QN, Stewart C, West S, Williamson KS, Zemlan F, and Hensley K
- Subjects
- Administration, Oral, Age Factors, Animals, Behavior, Animal drug effects, Behavior, Animal physiology, Blotting, Northern methods, Blotting, Western methods, Body Mass Index, Cell Line, Curcumin pharmacology, Dose-Response Relationship, Drug, Drug Interactions, Enzyme Inhibitors pharmacology, Enzyme-Linked Immunosorbent Assay methods, Glial Fibrillary Acidic Protein metabolism, Humans, Immunohistochemistry methods, Inhibitory Concentration 50, Masoprocol therapeutic use, Mice, Mice, Transgenic physiology, Microglia physiology, Models, Neurological, Motor Activity drug effects, Nitric Oxide metabolism, Paralysis genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction methods, Rotarod Performance Test methods, Spinal Cord cytology, Spinal Cord drug effects, Spinal Cord metabolism, Statistics, Nonparametric, Superoxide Dismutase genetics, Superoxide Dismutase physiology, Survival physiology, Tumor Necrosis Factor-alpha pharmacology, tau Proteins metabolism, Lipoxygenase Inhibitors pharmacology, Lipoxygenase Inhibitors therapeutic use, Masoprocol pharmacology, Microglia drug effects, Paralysis drug therapy, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc-superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up-regulation of tumor necrosis factor alpha (TNFalpha) and its primary receptor TNF-RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFalpha antagonists. Walker EOC-20 microglia cells were stimulated with recombinant TNFalpha, with or without inhibitors, and the cell response was indexed by NO2- output. Three hundred and fifty-five rationally selected compounds were included in this bioassay. The arachidonic acid 5-lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non-cytotoxic antagonists tested (IC50 8 +/- 3 microm). Investigation of the G93A-SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A-SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Disease-associated gliosis and cleaved microtubule-associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFalpha antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.
- Published
- 2004
- Full Text
- View/download PDF
3. Anti-inflammatory effects of tocopherol metabolites.
- Author
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Grammas P, Hamdheydari L, Benaksas EJ, Mou S, Pye QN, Wechter WJ, Floyd RA, Stewart C, and Hensley K
- Subjects
- Animals, Cells, Cultured, Dinoprostone metabolism, Dose-Response Relationship, Drug, Endothelial Cells cytology, Endothelial Cells metabolism, Lipopolysaccharides pharmacology, Mice, Microglia cytology, Microglia metabolism, Nitrites metabolism, Rats, Tumor Necrosis Factor-alpha pharmacology, Anti-Inflammatory Agents pharmacology, Antioxidants pharmacology, Endothelial Cells drug effects, Microglia drug effects, Tocopherols pharmacology
- Abstract
Our objective was to assess the anti-inflammatory effects of alpha-tocopherol, gamma-tocopherol, and their metabolites 2,5,7,8-tetramethyl-2-(beta-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2,7,8-trimethyl-2-(beta-carboxyethyl)-6-hydroxychroman (gamma-CEHC) in defined cell culture systems. Rat aortic endothelial cells and mouse microglial cultures were treated with tumor necrosis factor TNFalpha or bacterial lipopolysaccharide (LPS) and nitrite and prostaglandin E(2) (PGE(2)) were measured. alpha-CEHC suppressed TNFalpha-stimulated nitrite production in both cell types, whereas both CEHC derivatives inhibited LPS-stimulated microglial nitrite efflux. Both alpha-CEHC and gamma-CEHC inhibited microglial PGE(2) production, but neither alpha- nor gamma-tocopherol was effective at inhibiting cytokine-stimulated inflammatory processes. These results show that the anti-inflammatory effects of tocopherols are highly cell type-, stimulus-, and endpoint-dependent.
- Published
- 2004
- Full Text
- View/download PDF
4. New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine.
- Author
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Hensley K, Benaksas EJ, Bolli R, Comp P, Grammas P, Hamdheydari L, Mou S, Pye QN, Stoddard MF, Wallis G, Williamson KS, West M, Wechter WJ, and Floyd RA
- Subjects
- Animals, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacology, Autonomic Nervous System Diseases metabolism, Autonomic Nervous System Diseases prevention & control, Cardiovascular Diseases metabolism, Cardiovascular Diseases prevention & control, Chromans chemistry, Humans, Neoplasms epidemiology, Neoplasms prevention & control, gamma-Tocopherol chemical synthesis, gamma-Tocopherol chemistry, Chromans metabolism, Chromans pharmacology, gamma-Tocopherol metabolism, gamma-Tocopherol pharmacology
- Abstract
Vitamin E (alpha-tocopherol or alphaT) has long been recognized as a classic free radical scavenging antioxidant whose deficiency impairs mammalian fertility. In actuality, alpha-tocopherol is one member of a class of phytochemicals that are distinguished by varying methylation of a chroman head group. Early studies conducted between 1922 and 1950 indicated that alpha-tocopherol was specific among the tocopherols in allowing fertility of laboratory animals. The unique vitamin action of alphaT, combined with its prevalence in the human body and the similar efficiency of tocopherols as chain-breaking antioxidants, led biologists to almost completely discount the "minor" tocopherols as topics for basic and clinical research. Recent discoveries have forced a serious reconsideration of this conventional wisdom. New and unexpected biological activities have been reported for the desmethyl tocopherols, such as gamma-tocopherol, and for specific tocopherol metabolites, most notably the carboxyethyl-hydroxychroman (CEHC) products. The activities of these other tocopherols do not map directly to their chemical antioxidant behavior but rather reflect anti-inflammatory, antineoplastic, and natriuretic functions possibly mediated through specific binding interactions. Moreover, a nascent body of epidemiological data suggests that gamma-tocopherol is a better negative risk factor for certain types of cancer and myocardial infarction than is a alpha-tocopherol. The potential public health implications are immense, given the extreme popularity of alphaT supplementation which can unintentionally deplete the body of gamma-tocopherol. These findings may or may not signal a major paradigm shift in free radical biology and medicine. The data argue for thorough experimental and epidemiological reappraisal of desmethyl tocopherols, especially within the contexts of cardiovascular disease and cancer biology.
- Published
- 2004
- Full Text
- View/download PDF
5. Oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells.
- Author
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Hamdheydari L, Christov A, Ottman T, Hensley K, and Grammas P
- Subjects
- Animals, Brain cytology, Cells, Cultured, Endothelial Cells cytology, Oxidation-Reduction, Rats, Brain drug effects, Brain metabolism, Endothelial Cells drug effects, Endothelial Cells metabolism, Lipoproteins, LDL pharmacology, Membrane Fluidity drug effects, Nitric Oxide metabolism, Reactive Oxygen Species metabolism
- Abstract
There is an increase in the generation of reactive oxygen species and nitric oxide in the cerebral microcirculation in Alzheimer's disease. The factors that cause this increase in oxidative stress have not been identified. Increasing evidence suggests that there are common mechanisms in atherosclerosis and Alzheimer's disease. The objective of this study was to determine the effects of oxidized low density lipoproteins (LDLs) on brain endothelial cells. Cultured rat brain endothelial cells were treated with either native LDL (10 microg/ml) or LDL oxidized in vitro using 4-hydroxy-2-nonenal (HNE-LDL) (10 microg/ml), for 24h. The results showed that HNE-LDL significantly increased production of nitric oxide (p<0.01), decreased membrane fluidity (p<0.05), and increased reactive oxygen species generation (p<0.01). These data demonstrate that oxidized LDLs affect nitric oxide and radical generation in brain endothelial cells and could contribute to cerebrovascular dysfunction in Alzheimer's disease.
- Published
- 2003
- Full Text
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6. Message and protein-level elevation of tumor necrosis factor alpha (TNF alpha) and TNF alpha-modulating cytokines in spinal cords of the G93A-SOD1 mouse model for amyotrophic lateral sclerosis.
- Author
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Hensley K, Fedynyshyn J, Ferrell S, Floyd RA, Gordon B, Grammas P, Hamdheydari L, Mhatre M, Mou S, Pye QN, Stewart C, West M, West S, and Williamson KS
- Subjects
- Amino Acid Substitution genetics, Amyotrophic Lateral Sclerosis enzymology, Amyotrophic Lateral Sclerosis genetics, Animals, Cytokines genetics, Cytokines physiology, Mice, Mice, Transgenic, RNA, Messenger biosynthesis, RNA, Messenger genetics, Spinal Cord metabolism, Superoxide Dismutase genetics, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha physiology, Amyotrophic Lateral Sclerosis metabolism, Cytokines biosynthesis, Disease Models, Animal, Superoxide Dismutase biosynthesis, Tumor Necrosis Factor-alpha biosynthesis
- Abstract
Recent data indicate that certain pro-inflammatory cytokines are transcriptionally upregulated in the spinal cords of G93A-SOD1 mice, a model of amyotrophic lateral sclerosis (ALS). We previously showed that the receptor for tumor necrosis factor alpha (TNF-R1) was notably elevated at late presymptomatic as well as symptomatic phases of disease (J. Neurochem. 82 (2002) 365). We now extend these findings by showing that message for TNFalpha, as well as mRNA for interferon gamma (IFNgamma) and transforming growth factor beta1/2 (TGFbeta1, TGFbeta2), is simultaneously increased. Furthermore, TNFalpha protein is significantly increased in G93A-SOD1 mouse spinal cords, as are protein levels for interleukin-6 (IL6), IFNgamma, and the chemokines RANTES (CCL5) and KC. The interaction of TNFalpha, IL6, and IFNgamma proteins was modeled in vitro using Walker EOC-20 murine microglia with nitrite (NO(2)(-)) efflux as a quantitative index of cell response. TNFalpha alone caused robust NO(2)(-) flux, while IL6 had a lesser effect and neither IFNgamma nor IL1beta was active when applied singly. The TNFalpha stimulus was potently magnified in the presence of IL6 or IFNgamma. When applied in combination at very low concentrations, IFNgamma co-synergized with IL6 to produce a multiplicative increase in NO(2)(-) after stimulation with TNFalpha. Taken together, these data suggest that modest increases in multiple synergistic cytokines could produce a disproportionately severe activation of microglia within the degenerating spinal cord. Our data support a model wherein TNFalpha acts as a principal driver for neuroinflammation, while several co-stimulating cytokines and chemokines act to potentiate the TNFalpha effects.
- Published
- 2003
- Full Text
- View/download PDF
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