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Biomedical subjects

Carroll E Cross

Publications and source records attributed to Carroll E Cross.

At least 19 recordsLinked to original sources
PubMed2005

Studies in humans using deuterium-labeled alpha- and gamma-tocopherols demonstrate faster plasma gamma-tocopherol disappearance and greater gamma-metabolite production.

We hypothesized that human plasma alpha- and gamma-tocopherol concentrations reflect differences in their kinetics, especially influenced by gamma-tocopherol metabolism. Vitamin E kinetics were evaluated in humans (n=14) using approximately 50 mg each of an equimolar ratio of d6-alpha- and d2-gamma-tocopheryl acetates administered orally. Mass spectrometry was used to measure deuterated plasma tocopherols, as well as plasma and urinary vitamin E metabolites, alpha- and gamma-carboxyethylhydroxychromans (CEHCs). Plasma d2-gamma-tocopherol fractional disappearance rates (FDR; 1.39+/-0.44 pools/day, mean+/-SD) were more than three times greater than those of d6-alpha-tocopherol (0.33+/-0.11, p<0.001). The d2-gamma-tocopherol half-life was 13+/-4 h compared with 57+/-19 for d6-alpha-tocopherol. Whereas neither plasma nor urinary d6-alpha-CEHC was detectable (limit of detection 1 nmol/L), gamma-CEHC (labeled plus unlabeled) increased from 129+/-20 to 258+/-40 nmol/L by 12 h and returned to baseline by 48 h; at 12 h d2-gamma-CEHC represented 54+/-4% of plasma gamma-CEHC. Women compared with men had a greater d2-gamma-tocopherol FDR (p<0.004) and a greater maximal plasma d2-gamma-CEHC concentration (p<0.02) and CEHC FDR (p<0.007), as well as excreting four times as much d2-gamma-CEHC (p<0.04) in urine. Thus, gamma-tocopherol is rapidly metabolized to gamma-CEHC, and to a greater degree in women than in men, whereas alpha-tocopherol is maintained in the plasma and little is metabolized to alpha-CEHC.

Adult↗
PubMed2005

Alpha-tocopherol modulates Cyp3a expression, increases gamma-CEHC production, and limits tissue gamma-tocopherol accumulation in mice fed high gamma-tocopherol diets.

Although all forms of vitamin E are absorbed, the liver preferentially secretes alpha-, but not gamma-tocopherol, into plasma. Liver alpha-tocopherol secretion is under the control of the alpha-tocopherol transfer protein (TTP). Therefore, to assess gamma-tocopherol bioactivities Ttpa-/-, +/- and +/+ mice were fed for 5 weeks diets containing gamma-tocopherol 550 (gamma-T550), gamma-tocopherol 60 (gamma-T60) mg/kg that also contained trace amounts of alpha-tocopherol, a vitamin E-deficient diet, or a control diet. Plasma and tissues from mice fed gamma-T550 diets were found to contain similar gamma- and alpha-tocopherol concentrations despite the high dietary gamma-tocopherol content; nervous tissues contained almost no gamma-tocopherol. Liver vitamin E metabolites (carboxyethyl hydroxychromans, CEHCs) were also measured. In mice with widely ranging liver alpha- (from 0.7 to 16 nmol/g) and gamma-tocopherol concentrations (0 to 13 nmol/g), hepatic alpha-CEHC was undetectable, but gamma-CEHC concentrations (0.1 to 0.8 nmol/g) were correlated with both alpha- and gamma-tocopherol concentrations (P < 0.004). Hepatic cytochrome P450s (CYPs) involved in vitamin E metabolism, Cyp4f and Cyp3a, were also measured. There were no variations in Cyp4f protein expression as related to diet or mouse genotype. However, Cyp3a was correlated (P < 0.0001) with liver alpha-, but not gamma-tocopherol concentrations. These data support the hypothesis that alpha-tocopherol modulates xenobiotic metabolism by increasing Cyp3a expression, gamma-CEHC formation, and the excretion of both gamma-tocopherol and gamma-CEHC.

Animal Feed↗
PubMed2004

Ascorbic acid in nasal and tracheobronchial airway lining fluids.

Ascorbic acid (AA) is thought to be an important antioxidant in the respiratory tract, whose regulation is yet to be fully characterized. We investigated whether AA in respiratory tract lining fluids (RTLFs) can be augmented by oral supplementation with AA. Plasma, nasal lavage fluids (NLFs), induced sputum (IS), and saliva were analyzed for AA immediately before and 2 h after ingestion of 2 g of AA in 13 healthy subjects. Concentrations of AA (median and range) were 52.5 (16.0-88.5), 2.4 (0.18-4.66), 2.4 (0.18-6.00), and 0.55 (0.18-18.90) micromol/l, respectively. Two hours after ingestion of AA, plasma AA increased 2-fold (p = .004), NLF AA increased 3-fold (p = .039), but IS and saliva AA did not increase. As AA concentrations in saliva and tracheobronchial secretions were low compared with other common extracellular components (such as urate), we evaluated the fate of AA in these fluids. Addition of AA to freshly obtained saliva or IS resulted in rapid depletion, which could be largely prevented or reversed by sodium azide or dithiothreitol. These findings suggest that oxidant-producing systems in saliva and airway secretions, such as heme peroxidases and other oxidizing substances, rapidly consume AA. Whereas oral supplementation resulted in detectable increases of AA in NLFs, its levels in tracheobronchial lining fluid, as measured by IS, were unaffected and remained relatively low, suggesting that AA may play a less significant antioxidant role in this compartment as compared with most other extracellular compartments.

Administration, Oral↗
PubMed2004

Tissue-specific gene expression of prolactin receptor in the acute-phase response induced by lipopolysaccharides.

Acute inflammation can elicit a defense reaction known as the acute-phase response (APR) that is crucial for reestablishing homeostasis in the host. The role for prolactin (PRL) as an immunomodulatory factor maintaining homeostasis under conditions of stress has been proposed; however, its function during the APR remains unclear. Previously, it was shown that proinflammatory cytokines characteristic of the APR (TNF-alpha, IL-1beta, and IFNgamma) induced the expression of the PRL receptor (PRLR) by pulmonary fibroblasts in vitro. Here, we investigated the in vivo expression of PRLR during lipopolysaccharide (LPS)-induced APR in various tissues of the mouse. We show that PRLR mRNA and protein levels were downregulated in hepatic tissues after intraperitoneal LPS injection. Downregulation of PRLR in the liver was confirmed by immunohistochemistry. A suppressive effect on mRNA expression was also observed in prostate, seminal vesicle, kidney, heart, and lung tissues. However, PRLR mRNA levels were increased in the thymus, and no changes were observed in the spleen. The proportion of transcripts for the different receptor isoforms (long, S1, S2, and S3) in liver and thymus was not altered by LPS injection. These findings suggest a complex tissue-specific regulation of PRLR expression in the context of the APR.

Acute-Phase Reaction↗
PubMed2004

Enhanced inflammatory responses in alpha-tocopherol transfer protein null mice.

The liver preferentially secretes alpha-tocopherol into plasma under the control of the hepatic alpha-tocopherol transfer protein (alpha-TTP). alpha-TTP-null mice (Ttpa(-/-) mice) are vitamin E deficient, therefore were used for investigations of in vivo responses to sub-normal tissue alpha-tocopherol concentrations during inflammation. Increased basal oxidative stress in Ttpa(-/-) mice was documented by increased plasma lipid peroxidation, and superoxide production by bone marrow-derived neutrophils stimulated in vitro with phorbol 12-myristate 13-acetate. Lipopolysaccharide (LPS) injected intraperitoneally induced increases in lung and liver HO-1 and iNOS, as well as plasma NO(x) in Ttpa(+/+) mice. LPS induced more modest increases in these markers in Ttpa(-/-) mice, while more marked increases in plasma IL-10 and lung lavage TNF alpha were observed. Taken together, these results demonstrate that alpha-tocopherol is important for proper modulation of inflammatory responses and that sub-optimal alpha-tocopherol concentrations may derange inflammatory-immune responses.

Animals↗
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

Lutein, zeaxanthin, macular pigment, and visual function in adult cystic fibrosis patients.

BACKGROUND: Pancreatic insufficiency in cystic fibrosis (CF), even with replacement pancreatic enzyme therapy, is often associated with decreased carotenoid absorption. Because the macular pigment of the retina is largely derived from 2 carotenoids, lutein and zeaxanthin, the decreased serum concentrations seen in CF may have consequences for ocular and retinal health OBJECTIVES: Our aims were to determine plasma carotenoid concentrations, determine absorption and distribution of macular pigment, and assess retinal health and visual function in CF patients. DESIGN: In 10 adult CF patients (ages 21-47 y) and 10 age- and sex-matched healthy control subjects, we measured macular pigment density in vivo, measured serum lutein and zeaxanthin concentrations, and comprehensively assessed visual performance (including contrast sensitivity, color discrimination, and retinal function) under conditions of daylight illumination. RESULTS: Serum lutein and zeaxanthin were significantly reduced (P < 0.005) in CF patients ( +/- SD: 87 +/- 36.1 and 27 +/- 15.8 nmol/L, respectively) compared with control subjects (190 +/- 72.1 and 75 +/- 23.6 nmol/L, respectively). Although macular pigment optical density was significantly lower (P < 0.0001) in the CF group (0.24 +/- 0.11) than in the control group (0.53 +/- 0.12), no significant differences in visual function were observed. CONCLUSIONS: Adults with CF have dramatically low serum and macular concentrations of carotenoids (lutein and zeaxanthin), but their ocular status and visual function are surprisingly good. The clinical implications of low plasma concentrations of carotenoids in CF are yet to be clarified.

Adult↗
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

5-nitro-gamma-tocopherol increases in human plasma exposed to cigarette smoke in vitro and in vivo.

We hypothesized that the high concentrations of reactive nitrogen species in cigarette smoke and the known stimulatory effects of cigarette smoke on the inflammatory immune systems would lead to the formation of 5-nitro-gamma-tocopherol (NGT). In order to assess gamma-tocopherol nitration, human plasma was exposed in vitro to gas phase cigarette smoke (GPCS) or air for up to 6 h. A liquid chromatography-mass spectrometry (LC-MS) method was developed to quantitate NGT. Detector response was linear from 0.1 to 3 pmol NGT, with a detection limit of 20 fmol. After a 1 h lag time, 6 h plasma exposure to GPCS depleted approximately 75% of alpha-T, approximately 60% of gamma-T and increased NGT from 3 to 134 nmol/l. The increase in NGT accounted for approximately 20% of the gamma-T decrease. NGT also correlated (R2 = 0.9043) with nitrate concentrations in GPCS-exposed plasma. The physiologic relevance of NGT was evaluated in a group of healthy humans. Smokers (n = 15) had plasma NGT concentrations double those of nonsmokers (n = 19), regardless of corrections using lipids or gamma-T; plasma alpha-T and gamma-T concentrations were similar between the groups. Our results show that LC-MS can be successfully used for NGT quantitation in biologic samples. Importantly, NGT in smokers' plasma suggests that cigarette smoking causes increased nitrosative stress.

Humans↗
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

Induction of stress proteins and MMP-9 by 0.8 ppm of ozone in murine skin.

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) on the cellular constituents of the underlying skin epidermis and dermis. In the present study, hairless mice exposed for 6 h to 0.8 ppm O(3) showed increases in lipid peroxidation, as quantitated by increases in 4-hydroxynonenal-protein adducts. O(3) exposure caused an induction of the stress proteins HSP27 and heme oxygenase-1 (HO-1), starting at 6 h and increasing up to 18 h after O(3) exposure. This was accompanied by an increase in matrix metalloproteinase-9 (MMP-9) mRNA and activity levels, indicative of possible injurious-reparative processes. Collectively, our data demonstrate that skin exposure to O(3) not only affects antioxidant levels and oxidation markers in the outermost stratum corneum layer, but also induces cellular stress responses in the deeper cellular layers of the skin.

Animals↗
PubMed2003

Ozone-induced disruptions of lung transcriptomes.

We have analyzed changes in approximately 4000 lung mRNAs, with GeneChips, in mice exposed to 1 ppm O(3) for three consecutive nights (8 h per night). Differential gene expression analysis identified approximately 260 O(3) sensitive genes; approximately 80% of these were repressed and approximately 20% were induced in O(3)-exposed mice compared to the air-exposed controls. A 20-fold induction of serum amyloid A3 mRNA by O(3) suggested activation of NF-kappaB and CCAAT/enhancer binding protein-mediated pathways by inflammatory cytokines. Induction (up to 14-fold) of 12 genes that increase DNA synthesis and cell cycle progression, and increase (approximately 7-fold) in CD44 mRNA and macrophage metalloelastase suggested a state of O(3)-induced hyperplasia and lung remodeling. Several mRNAs encoding enzymes of xenobiotic metabolism and cytoskeletal functions were repressed and may suggest cytokine mediated suppression of cytochrome P450 expression and cachexia-like inflammatory state in ozone-exposed lungs. The expressions of approximately 30 genes of immune response were also repressed. Collectively this genome-wide analysis of lungs identified ozone-induced disruption of gene transcriptional profile indicative of increased cellular proliferation under suppressed immune surveillance and xenobiotic metabolism.

Air↗
PubMed2003

Cytokine induction of prolactin receptors mediates prolactin inhibition of nitric oxide synthesis in pulmonary fibroblasts.

Prolactin (PRL) has been implicated as a modulator of immune function, and some of its actions may be linked to NO synthesis. Because NO acts as a mediator of inflammation, we speculated that an inflammatory milieu could unmask pathways by which PRL could affect NO synthesis. Here, we show that pro-inflammatory cytokines induce the expression of PRL receptors in pulmonary fibroblasts, allowing PRL to inhibit cytokine-induced NO production and the expression of the inducible nitric oxide synthase (iNOS). Inhibition of iNOS expression by PRL correlates with the phosphorylation of STAT-5b (signal transducer and activator of transcription 5b) and the suppression of expression of IRF-1 (interferon regulatory factor 1), a transcription factor for iNOS. These results reveal previously unrecognized mechanisms by which PRL and PRL receptors may play significant modulatory roles during immune-inflammatory processes.

Animals↗
PubMed2003

Inhibition of oral peroxidase activity by cigarette smoke: in vivo and in vitro studies.

Oral peroxidase (OPO), the pivotal enzyme in the salivary antioxidant system, seems to be of paramount importance in the oral defense mechanism, especially against the attack of free radicals related to cigarette smoke (CS) and the evolution of oral cancer. The major inducer of oral cancer is exposure to tobacco, which is responsible for 50-90% of cases worldwide. The purpose of our study was to elucidate the outcome of interaction between CS and OPO in smokers and nonsmokers. After smoking a single cigarette, a sharp drop of OPO activity was observed in both groups: 42.5% in smokers and 58.5% in nonsmokers (p <.05). After 30 min, the level of activity returned to 90-100% of the presmoking level, presumably due to the secretion of new saliva into the oral cavity. The difference between the two groups was also observed after exposure of saliva to one cigarette in smoking flasks (in vitro studies); however, as expected, no recovery of activity was observed in either group. Similarly, the OPO activity loss was accompanied by increased carbonylation of the salivary proteins, an indicator of the oxidative damage to proteins. These results may be of great clinical importance, as heavy smokers smoke 20 cigarettes or more on a daily basis. Accordingly, most of the time the oral epithelium of heavy smokers is essentially unprotected by OPO against the deleterious effects of thiocyanate ions and hydroxyl radicals produced by unremoved hydrogen peroxide in the presence of the salivary redox-active metal ions. This may pave the way for the CS-induced and saliva-mediated initiation and progression of oral cancer.

Antioxidants↗
PubMed2003

Smoking and exposure to environmental tobacco smoke decrease some plasma antioxidants and increase gamma-tocopherol in vivo after adjustment for dietary antioxidant intakes.

BACKGROUND: 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. OBJECTIVE: We compared the effects on plasma antioxidant concentrations in cotinine-confirmed active and passive smokers with those in nonsmokers, independent of differences in dietary intakes and other covariates. DESIGN: Plasma samples from 83 smokers, 40 passive smokers, and 36 nonsmokers were analyzed for total ascorbic acid, alpha- and gamma-tocopherols, 5 carotenoids, retinol, and cotinine. Groups were compared by using analysis of variance with adjustment for sex, age, race, body mass index, alcohol intake, triacylglycerol concentration, fruit and vegetable intakes, and dietary antioxidants. RESULTS: After adjustment for dietary antioxidant intakes and other covariates, smokers and passive smokers had significantly lower plasma beta-carotene concentrations than did nonsmokers (0.15, 0.17, and 0.24 micro mol/L, respectively) and significantly higher gamma-tocopherol concentrations (7.8, 7.8, and 6.5 micro mol/L, respectively). Smokers had significantly lower plasma ascorbic acid and beta-cryptoxanthin concentrations than did nonsmokers and passive smokers (ascorbic acid: 43.6, 54.5, and 54.6 micro mol/L, respectively; beta-cryptoxanthin: 0.12, 0.16, and 0.16 micro mol/L, respectively) and significantly lower concentrations of lutein and zeaxanthin than did nonsmokers (0.33 compared with 0.41 micro mol/L). The P values for all the differences described above were < 0.05. No significant differences in plasma concentrations of alpha-tocopherol, alpha-carotene, total carotenoids, lycopene, or retinol were observed. CONCLUSIONS: These results indicate that cigarette smokers and nonsmokers exposed to cigarette smoke have a significantly lower plasma antioxidant status than do unexposed nonsmokers, independent of differences in dietary antioxidant intakes. Further research is required to explain why plasma gamma-tocopherol concentrations were significantly higher in smokers and passive smokers than in nonsmokers.

Adult↗
PubMed2003

Lycopene inhibits the growth of normal human prostate epithelial cells in vitro.

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 epithelial cells (PrEC) by treating them with synthetic all-E-lycopene (up to 5 micromol/L) and assessing proliferation via [3H]thymidine incorporation. The effects of lycopene on cell cycle progression were investigated via flow cytometry. To elucidate whether lycopene modulates cyclins involved in cell cycle progression, protein expressions of cyclins D1 and E were analyzed. The results show that lycopene significantly inhibited the growth of PrEC in a dose-dependent fashion. Flow cytometry revealed a significant cell cycle arrest in the G0/G1 phase. This effect was confirmed by inhibition of cyclin D1 protein expression, whereas cyclin E levels remained unchanged. The results demonstrate that lycopene inhibits growth of nonneoplastic PrEC in vitro. We hypothesize that lycopene might likewise inhibit the growth of prostatic epithelial cells in vivo. This might have an effect on prostate development and/or on enlargement of prostate tissue as found in benign prostate hyperplasia, a potential precursor of prostate cancer.

Antioxidants↗