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Biomedical subjects

G E Gibson

Publications and source records attributed to G E Gibson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype.

Brain metabolism and the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a mitochondrial enzyme, are diminished in brains from patients with Alzheimer's disease (AD). In 109 subjects, the Clinical Dementia Rating (CDR) score was highly correlated with brain KGDHC activity. In AD patients who carried the epsilon 4 allele of the apolipoprotein E gene (ApoE4), the CDR score correlated better with KGDHC activity than with the densities of neuritic plaques or neuritic tangles. In contrast, in patients without ApoE4, the CDR score correlated significantly better with tangles and plaques than with KGDHC activity. The results suggest that mitochondrial/oxidative damage may be more important for the cognitive dysfunction in AD patients who carry ApoE4 than in those who do not.

Aged↗
PubMed1999

Inhibition of select mitochondrial enzymes in PC12 cells exposed to S-(1,1,2,2-tetrafluoroethyl)-L-cysteine.

Many halogenated foreign compounds are detoxified by conversion to the corresponding cysteine S-conjugate, which is N-acetylated and excreted. However, several halogenated cysteine S-conjugates [e.g. S-(1,1,2,2-tetrafluoroethy)-L-cysteine (TFEC)] are converted to mitochondrial toxicants by cysteine S-conjugate beta-lyases. In the present work, we showed that TFEC appreciably inactivated highly purified alpha-ketoglutarate dehydrogenase complex (KGDHC) in the presence of a cysteine S-conjugate beta-lyase. Incubation of PC12 cells (which contain endogenous cysteine S-conjugate beta-lyase activity) with TFEC led to a concentration- and time-dependent loss of endogenous KGDHC activity. A 24-hr exposure to 1 mM TFEC decreased KGDHC activity in the cells by 90%. Although treatment with TFEC did not inhibit intrinsic pyruvate dehydrogenase complex (PDHC) activity, it inhibited dichloroacetate/Mg2+-mediated activation/dephosphorylation of PDHC in the PC12 cells by 90%. To determine the selectivity of enzymes targeted by TFEC, several cytosolic and mitochondrial enzymes involved in energy metabolism [malate dehydrogenase, glyceraldehyde 3-phosphate dehydrogenase, glutamate dehydrogenase, lactate dehydrogenase, cytosolic and mitochondrial aspartate aminotransferases (AspAT)] were also assayed in the PC12 cells exposed to 1 mM TFEC for 24 hr. Of these enzymes, only mitochondrial AspAT, a key enzyme of the malate-aspartate shuttle, was inhibited. The present results demonstrate a selective vulnerability of mitochondrial enzymes to toxic cysteine S-conjugates. The data indicate that TFEC may be a useful cellular/mitochondrial toxicant for elucidating the consequences of the diminished mitochondrial function that accompanies numerous neurodegenerative diseases.

Animals↗
PubMed1999

Cultures of astrocytes and microglia express interleukin 18.

Interleukin 18 (IL-18 or interferon-gamma inducing factor) is a recently discovered pro-inflammatory cytokine and powerful stimulator of the cell-mediated immune response. IL-18 is produced by several sources including monocytes/macrophages, keratinocytes and the zona reticularis and zona fasciculata of the adrenal cortex. IL-18 occurs in brain but its cellular source in the CNS has never been investigated. The presence of IL-18 and its response to stimulation in the brain was tested with primary cultures of microglia, astrocytes and hippocampal neurons. IL-18 mRNA was present in astrocytes and microglia, but not in neurons. The endotoxin lipopolysaccharide (LPS) did not affect IL-18 in astrocytes, but LPS robustly increased IL-18 mRNA in microglia. IL-18 protein was constitutively expressed in astrocytes and induced in microglia by LPS. The levels of interleukin-1beta converting enzyme (ICE), an activating enzyme, and caspase 3 (CPP32), an inactivating enzyme, were assessed to investigate the presence of the appropriate processing enzymes in the cultured cells. ICE was present at constitutive levels in microglia and astrocytes suggesting that these cell types may produce and secrete matured IL-18. Active forms of CPP32 were not detectable in either cell type indicating the absence of a degradative pathway of IL-18. The present results demonstrate that microglia and astrocytes are sources of brain IL-18 and add a new member to the family of cytokines produced in the brain.

Animals↗
PubMed1999

Protein-bound acrolein: a novel marker of oxidative stress in Alzheimer's disease.

Several lines of evidence support the role of oxidative stress, including increased lipid peroxidation, in the pathogenesis of Alzheimer's disease (AD). Lipid peroxidation generates various reactive aldehydes, such as 4-hydroxynonenal (HNE), which have been detected immunochemically in AD, particularly in neurofibrillary tangles, one of the major diagnostic lesions in AD brains. A recent study demonstrated that acrolein, the most reactive among the alpha,beta-unsaturated aldehyde products of lipid peroxidation, could be rapidly incorporated into proteins, generating a carbonyl derivative, a marker of oxidative stress to proteins. The current studies used an antibody raised against acrolein-modified keyhole limpet hemocyanin (KLH) to test whether acrolein modification of proteins occurs in AD. Double immunofluorescence revealed strong acrolein-KLH immunoreactivity in more than half of all paired helical filament (PHF)-1-labeled neurofibrillary tangles in AD cases. Acrolein-KLH immunoreactivity was also evident in a few neurons lacking PHF-1-positive neurofibrillary tangles. Light acrolein-KLH immunoreactivity occurred in dystrophic neurites surrounding the amyloid-beta core, which itself lacked acrolein-KLH staining. The pattern of acrolein-KLH immunostaining was similar to that of HNE. Control brains did not contain any acrolein-KLH-immunoreactive structures. The current results suggest that protein-bound acrolein is a powerful marker of oxidative damage to protein and support the hypothesis that lipid peroxidation and oxidative damage to protein may play a crucial role in the formation of neurofibrillary tangles and to neuronal death in AD.

Acrolein↗
PubMed1999

Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia.

Microglial activation, oxidative stress, and dysfunctions in mitochondria, including the reduction of cytochrome oxidase activity, have been implicated in neurodegeneration. The current experiments tested the effects of reducing cytochrome oxidase activity on the ability of microglia to respond to inflammatory insults. Inhibition of cytochrome oxidase by azide reduced oxygen consumption and increased reactive oxygen species (ROS) production but did not affect cell viability. Azide also attenuated microglial activation, as measured by nitric oxide (NO.) production in response to lipopolysaccharide (LPS). It is surprising that the inhibition of cytochrome oxidase also diminished the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a Krebs cycle enzyme. This reduction was exaggerated when the azide-treated microglia were also treated with LPS. The combination of the azide-stimulated ROS and LPS-induced NO. would likely cause peroxynitrite formation in microglia. Thus, the possibility that KGDHC was inactivated by peroxynitrite was tested. Peroxynitrite inhibited the activity of isolated KGDHC, nitrated tyrosine residues of all three KGDHC subunits, and reduced immunoreactivity to antibodies against two KGDHC components. Thus, our data suggest that inhibition of the mitochondrial respiratory chain diminishes aerobic energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vulnerable to NO. and peroxynitrite that result from microglial activation. Thus, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.

Animals↗
PubMed1999

Oxidative stress is associated with region-specific neuronal death during thiamine deficiency.

Thiamine deficiency (TD) is a model of chronic impairment of oxidative metabolism and selective neuronal loss. TD leads to region-specific neuronal death and elevation of inducible nitric oxide synthase (iNOS) in macrophages/microglia in mouse brain. Identification of the initial site of neuronal death in the submedial thalamic nucleus allowed us to test the role of iNOS and oxidative stress in TD-induced neuronal death. The pattern of neuronal loss, which begins after 9 days of TD, overlapped with induction of the oxidative stress marker heme oxygenase-1 (HO-1) in microglia. Neuronal death and microglial HO-1 induction spread to engulf the whole thalamus after 11 days of TD. As in past studies, reactive iron and ferritin accumulated in microglia beginning on day 10. The lipid peroxidation product, 4-hydroxynonenal (HNE) accumulated in the remaining thalamic neurons only after 11 days of TD. These responses were not likely mediated by iNOS because HO-1 induction and HNE accumulation were comparable in iNOS knockout mice and wild-type controls. These results show that region and cell specific oxidative stress is associated with selective neurodegeneration during TD. Thus, TD is a useful model to help elucidate neuron-microglial interaction in neurodegenerative diseases associated with oxidative stress.

Aldehydes↗
PubMed1999

Oxidative stress and a key metabolic enzyme in Alzheimer brains, cultured cells, and an animal model of chronic oxidative deficits.

Oxidative stress and diminished metabolism occur in several neurodegenerative disorders. Brains from Alzheimer's disease (AD) patients exhibit several indicators of oxidative stress and have reduced activities of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a key mitochondrial enzyme. Whether these abnormalities are secondary to neurodegenerative processes or are inherent properties of the cells cannot be determined in autopsy brain. Studies in cultured fibroblasts suggest that AD-related differences in oxidative stress and KGDHC reflect inherent properties of AD cells. KGDHC is sensitive to oxidative stress whether the enzyme is studied in cells, in purified mitochondria, or as an isolated protein. Reductions of brain KGDHC in living rodents lead to oxidative stress and selective cell death. The results suggest that KGDHC participates in a deleterious cascade of events related to oxidative stress that are critical in selective neuronal loss in neurodegenerative diseases.

Alzheimer Disease↗
PubMed1998

A stringent test for the nucleotide switch mechanism of carbamoyl phosphate synthetase.

Carbamoyl phosphate synthetase (CPS) catalyzes the formation of carbamoyl phosphate from bicarbonate, glutamine, and two molecules of MgATP. The X-ray crystal structure of the enzyme has revealed that the two nucleotide binding sites are separated by approximately 35 A. Isotopic oxygen exchange of 18O and 16O between solvent water and [13C]bicarbonate was measured using 13C NMR spectroscopy during substrate turnover in the presence and absence of glutamine as a nitrogen source. In the absence of added glutamine, CPS catalyzed the exchange of one oxygen atom from bicarbonate with solvent water during every turnover of the bicarbonate-dependent ATPase reaction. In the presence of added glutamine, there was no exchange of solvent water with bicarbonate during the enzymatic synthesis of carbamoyl phosphate, indicating that any carbon-containing intermediate in the reaction mechanism is committed to the formation of carbamoyl phosphate and is not subject to hydrolysis. These results are fully consistent with a chemical mechanism that requires the physical migration of the carbamate intermediate from the site of its formation within one of the nucleotide binding domains to the other nucleotide binding domain for subsequent phosphorylation by the second MgATP. These results are not compatible with a nucleotide switch mechanism. The nucleotide switch mechanism includes the synthesis of carbamoyl phosphate entirely within a single nucleotide binding domain and concurrent conformational changes driven by the bicarbonate-dependent hydrolysis of MgATP at the second nucleotide binding domain.

Adenosine Triphosphatases↗
PubMed1998

Alpha-ketoglutarate dehydrogenase in Alzheimer brains bearing the APP670/671 mutation.

Alzheimer's disease (AD) is associated with a striking reduction in the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC). The deficiency occurs in brains from AD patients of undefined etiology, and in fibroblasts from both sporadic and familial AD cases. To further assess the nature of the abnormality of KGDHC in AD, KGDHC activities and immunoreactivities were analyzed in brains from AD patients bearing the Swedish APP670/671 mutation. This gene defect causes overproduction of the amyloid beta peptide. KGDHC activities were reduced by 55 to 57% compared with control values in the mutation-bearing AD cases in the medial temporal and superior frontal cortices. The immunochemical levels of KGDHC subunits Elk (-51%) and E2k (-76%) declined, whereas E3 concentrations were unchanged. The results suggest that mitochondrial dysfunction is a part of the pathophysiological process in AD even when the primary pathogenic cause is nonmitochondrial.

Acyltransferases↗
PubMed1998

Abnormalities of mitochondrial enzymes in Alzheimer disease.

Abundant evidence, including critical information gathered by Prof. Siegfried Hoyer and his colleagues, indicates that abnormalities of cerebral metabolism are common in neurodegenerative diseases, including Alzheimer's Disease (AD). Alterations in mitochondrial enzymes likely underlie these deficits. Replicable reductions in AD brain occur in the pyruvate dehydrogenase complex (the link of glycolysis to the Kreb's cycle), the alpha-ketoglutarate dehydrogenase complex (KGDHC; the link of Kreb's cycle to glutamate metabolism) and cytochrome oxidase (the link of the Kreb's cycle to oxygen utilization). Available evidence suggests that deficiencies in KGDHC may be genetic in some cases, whereas evidence that the other two enzyme systems have a genetic component is lacking. Additional results indicate that the reductions can also be secondary to other causes including oxidative stress. A variety of data suggest that the mitochondrial insufficiencies contribute significantly to the pathophysiology of AD.

Alzheimer Disease↗
PubMed1998

Induction of nitric oxide synthase and microglial responses precede selective cell death induced by chronic impairment of oxidative metabolism.

Abnormal oxidative processes including a reduction in thiamine-dependent enzymes accompany many neurodegenerative diseases. Thiamine deficiency (TD) models the cellular and molecular mechanisms by which chronic oxidative aberrations associated with thiamine-dependent enzyme deficits cause selective neurodegeneration. The mechanisms underlying selective cell death in TD are unknown. In rodent TD, the earliest region-specific pathological change is breakdown of the blood-brain barrier (BBB). The current studies tested whether nitric oxide and microglia are important in the initial events that couple BBB breakdown to selective neuronal loss. Enhanced expression of endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate diaphorase reactivity in microvessels, as well as the presence of numerous inducible nitric oxide synthase-immunoreactive microglia, accompanied the increases in BBB permeability. Nitric oxide synthase induction appears critical to TD pathology, because immunoreactivity for nitrotyrosine, a specific nitration product of peroxynitrite, also increased in axons of susceptible regions. In addition, TD elevated iron and the antioxidant protein ferritin in microvessels and in activated microglia, suggesting that these cells are responding to an oxidative challenge. All of these changes occurred in selectively vulnerable regions, preceding neuronal death. These findings are consistent with the hypothesis that the free radical-mediated BBB alterations permit entry of iron and extraneuronal proteins that set in motion a cascade of inflammatory responses culminating in selective neuronal loss. Thus, the TD model should help elucidate the relationship between oxidative deficits, BBB abnormalities, the inflammatory response, ferritin and iron elevation, and selective neurodegeneration.

Animals↗
PubMed1998

Coexistence of lupus erythematosus and porphyria cutanea tarda in fifteen patients.

BACKGROUND: Lupus erythematosus (LE) and porphyria cutanea tarda (PCT) may have similar clinical presentations, and their coexistence presents special problems in diagnosis and management. OBJECTIVE: The purposes of this study were to describe a patient with discoid LE and PCT and to present a review of 15 patients with coexistent LE (all variants) and PCT. METHODS: The medical records of all patients with coexistent LE and PCT seen between 1976 and 1995 were retrospectively reviewed. RESULTS: Of 6179 cases of LE and 676 cases of porphyria (all variants), there were 15 patients, 6 men and 9 women, with coexistent LE and PCT. The mean age at diagnosis of LE was 42.8 years and of PCT was 48 years. Nine patients had discoid LE; five patients had systemic LE, and one patient had subacute cutaneous LE. The initial diagnosis was LE in eight patients, PCT in five patients, and simultaneous LE and PCT in two patients. Precipitating factors for PCT included alcohol in seven patients, iron overload in one patient, and estrogen in one patient. Treatment of LE with hydroxychloroquine 200 mg daily precipitated PCT in two patients. Patients were treated with phlebotomy or low-dose antimalarials for PCT. Patients with systemic LE received systemic glucocorticoid therapy. Patients with discoid LE and subacute cutaneous LE were treated with topical glucocorticoids. CONCLUSION: The association of LE and PCT poses therapeutic challenges. The preferred treatment for one may exacerbate the other. Use of standard dose antimalarials for LE is inadvisable, and phlebotomy or low-dose antimalarials should be used cautiously in patients with coexistent disease.

Adult↗
PubMed1998

Immunochemical characterization of the deficiency of the alpha-ketoglutarate dehydrogenase complex in thiamine-deficient rat brain.

Mitochondrial dysfunction is a common feature of many neurodegenerative disorders. The metabolic encephalopathy caused by thiamine deficiency (TD) is a classic example in which an impairment of cerebral oxidative metabolism leads to selective cell death. In experimental TD in rodents, a reduction in the activity of the thiamine diphosphate-dependent, mitochondrial enzyme alpha-ketoglutarate dehydrogenase complex (KGDHC) occurs before the onset of pathologic lesions and is among the earliest biochemical deficits found. To understand the molecular basis and the significance of the deficiency of KGDHC in TD-induced brain damage, the enzyme activity and protein levels of KGDHC were analyzed. The effect of TD on the subregional/cellular distribution of KGDHC and the anatomic relation of KGDHC with selective cell death were also tested by immunocytochemistry. Consistent with several previous studies, TD dramatically reduced KGDHC activity in both anatomically damaged (thalamus and inferior colliculus) and spared (cerebral cortex) regions. Immunocytochemistry revealed no apparent correlation of regional KGDHC immunoreactivity or its response to TD with affected regions in TD. The basis of the enzymatic and immunocytochemical behavior of KGDHC was further assessed by quantitative immunoblots, using antibodies specific for each of the three KGDHC components. Despite the marked decrease of KGDHC activity in TD, no reduction of any of the three KGDHC protein levels was found. Thus, TD impairs the efficacy of the KGDHC catalytic machinery, whereas the concentration of protein molecules persists. The generalized decline of KGDHC activity with no apparent anatomic selectivity is consistent with the notion that the compromised mitochondrial oxidation sensitizes the brain cells to various other insults that precipitate the cell death. The current TD model provides a relevant experimental system to understand the molecular basis of many neurodegenerative conditions in which mitochondrial dysfunction and KGDHC deficiency are prominent features.

Alcohol Amnestic Disorder↗
PubMed1998

Disturbances of the blood-brain barrier without expression of amyloid precursor protein- containing neuritic clusters or neuronal loss during late stages of thiamine deficiency in guinea pigs.

Generalized oxidative deficits associated with experimental thiamine deficiency (TD) lead to selective neurodegeneration. In mouse brain, TD produces region-specific breach of the blood-brain barrier (BBB), neuronal loss and an accumulation of amyloid precursor protein (APP) in abnormal neurites. The APP-laden abnormal neurites within the damaged areas of mouse brain aggregate into neuritic clusters which strikingly resemble the neuritic component of Alzheimer amyloid plaques. However, amyloid beta-peptide (Abeta) immunoreactivity has not been demonstrated in these neuritic clusters, possibly because the Abeta region of APP in mice contains three amino acid substitutions as compared with the amino acid sequence of human Abeta. In contrast, the guinea pig nucleic acid sequence is more related to the human sequence and the Abeta region is identical in sequence to that of human APP. Thus, the current studies tested whether the presence of an authentic Abeta fragment of APP (i.e., identical to that of man) might make guinea pigs more vulnerable to the development of Abeta-containing neuritic clusters following TD. During late stages of TD, BBB abnormalities, manifested by immunoglobulin G (IgG) extravasation and increased NADPH diaphorase reactivity in microvessels, occurred in brain areas known to be damaged by TD in mice. However, despite the prolonged thiamine deprivation and the advanced neurological symptoms of guinea pigs, no significant neuronal loss or altered APP/Abeta immunostaining occurred in any brain region. Microglial activation, another early marker of damage in mice, was not evident in thiamine-deficient guinea pig brain. Ferritin immunoreactivity and iron deposition in oligodendrocytes within areas of BBB abnormalities were either slightly enhanced or unchanged as compared to controls. This is the first report of brain abnormalities in the guinea pig model of dietary and pyrithiamine-induced TD. The results demonstrate species differences in the response to TD-induced damage, and further support the role of BBB and nitric oxide in the initial events in TD pathology.

Amyloid beta-Peptides↗
PubMed1998

Low-dose retinoid therapy for chemoprophylaxis of skin cancer in renal transplant recipients.

BACKGROUND: Renal transplant recipients have an increased incidence of skin cancers, which may be multiple and aggressive. OBJECTIVES: The purpose of this study was to examine the chemoprophylactic effects of low-dose etretinate (0.3 mg/kg/day) on skin cancer development in renal transplant recipients and to monitor retinoid toxic effects at this dose. METHODS: All skin lesions were counted and photographed prior to therapy with etretinate. Patients were assessed at monthly intervals for new skin lesions and for retinoid toxicity. RESULTS: Eleven renal transplant recipients participated. There was a significant reduction in the number of skin cancers which occurred during etretinate therapy compared with pre-treatment for 3 and 6 months of treatment, and a trend towards fewer skin cancers in the 12 and 18 month treatment periods. Side-effects were well-tolerated and no significant biochemical effects were observed. CONCLUSION: Low dose etretinate is safe, well-tolerated and partially effective in chemoprophylaxis of skin cancer in renal transplant recipients.

Adult↗
PubMed1998

Langerhans cells in benign, premalignant and malignant skin lesions of renal transplant recipients and the effect of retinoid therapy.

BACKGROUND AND DESIGN: Langerhans cells (LC) are a unique population of antigen-presenting cells in the epidermis which may play a role in the defense mechanisms against skin tumors. Renal transplant recipients (RTRs) have a significantly increased incidence of premalignant and malignant skin lesions. Langerhans cells, which are important for local immune surveillance, may be depleted or downregulated in skin neoplasms of RTRs, facilitating their growth. We investigated the Langerhans cell densities in 29 squamous cell carcinomas (SCCs), five basal cell carcinomas (BCCs), four Bowen's disease, eight dysplastic lesions (actinic keratoses), and three viral warts from 15 RTRs and compared these to the Langerhans cell densities in normal control skin. Eleven RTRs were receiving low-dose etretinate as chemoprophylaxis for recurrent skin cancer and the effect of low-dose retinoid therapy on Langerhans cell densities in SCCs from these patients was also assessed. Langerhans cells in frozen tissue sections were stained with the anti-human Leu-6 monoclonal antibody. RESULTS: There was no significant difference in LC numbers between normal skin from RTRs and normal skin from non-immunosuppressed individuals. There was a statistically significant reduction in LC/mm2 and LC/1000 K (keratinocytes) for SCC, BCC, dysplastic lesions and viral warts compared with normal skin (P < 0.001, P < 0.01, P < 0.001, P < 0.05, respectively). There was a trend for an increase in Langerhans cell density in SCCs which developed during etretinate therapy compared with pre-etretinate but the difference was not statistically significant. CONCLUSIONS: In this study of RTRs, a significant reduction in Langerhans cell densities was observed in SCCs, BCCs and dysplastic lesions compared with normal skin. A reduction in Langerhans cell density in viral warts from RTRs was also observed. A working hypothesis may include a multifactorial etiology for this reduction in Langerhans cell densities. It is possible that human papilloma virus (HPV) infection, by reducing intraepidermal Langerhans cell density, may decrease local immune surveillance and facilitate the development of skin cancers. Ultraviolet radiation and immune suppression may also play a role. The marked depletion of Langerhans cells in skin cancers, precursor lesions and viral warts suggests a central role for Langerhans cells in skin cancer promotion in RTRs.

Basal Cell Carcinoma↗
PubMed1997

Importance of vascular changes in selective neurodegeneration with thiamine deficiency.

These results demonstrate that early alterations in the BBB may underlie selective vulnerability in this model of chronic reduced oxidative metabolism. Changes in the BBB (IgG extravasation) precede alterations in APP processing and cell death. Since thiamine-dependent enzymes are also reduced in the brain in Alzheimer's disease, similar processes may be important in the pathophysiology of the disease.

Amyloid beta-Protein Precursor↗