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Biomedical subjects

Rune Blomhoff

Publications and source records attributed to Rune Blomhoff.

At least 37 records · Page 2Linked to original sources
PubMed2005

Post-radiotherapy plasma total glutathione is associated to outcome in patients with head and neck squamous cell carcinoma.

We have studied the role of systemic oxidative stress for survival of patients with head and neck squamous cell carcinomas (HNSCC). Patients with lowest plasma total GSH levels had the lowest 36 months survival. In patients with post-radiotherapy concentrations of plasma total GSH less than median value, about 73% died during the 36 months follow-up compared to about 21% of patients with GSH values above median. Systemic oxidative stress as assessed by low GSH in post-radiotherapy plasma is associated to outcome in HNSCC patients.

Adult↗
PubMed2005

Exposure to retinyl esters, retinol, and retinoic acids in non-pregnant women following increasing single and repeated oral doses of vitamin A.

BACKGROUND: High intakes of vitamin A cause congenital malformations in experimental animals with elevated generation of retinoic acids (RA). Results in humans are conflicting. OBJECTIVE: To evaluate plasma concentration-time curves of retinyl esters, retinol and their metabolites at increasing doses of vitamin A. METHODS: An open-label dose-response study. Non-pregnant females (3 groups with n = 12; 18-40 years) received once daily oral doses of vitamin A palmitate up to 30,000 IU/day over 21 days. The area under the plasma concentration-time curve (AUC(24h)) served as indicator for exposure. RESULTS: AUC(24h) of retinyl esters increased linearly with dose. Retinol concentrations were unaffected. All-trans RA exhibited a diurnal-like concentration-time profile (Cmax at 3 h; Cmin at 8 h), concentrations decreasing below pre-dose levels at 5 h and regaining pre-dose levels at 16 h. The maximum temporary increase in exposure was 33% (single dose) and 19% (repeated doses) above baseline, but AUC(24h) remained unaltered. AUC(24h) increased linearly with dose for 13-cis RA and 13-cis-4-oxo RA. Repeated doses caused a 25% increase in exposure with the highest vitamin A intake. Accumulation of 13-cis-4-oxo RA at 30,000 IU/day doubled compared to the 4,000 IU/day intake. CONCLUSION: Repeated oral doses of up to 30,000 IU of vitamin A in addition to dietary vitamin A were without safety concern. Safe doses are probably higher, since plasma concentrations and exposure to RA remained at levels earlier shown to be without increased risk of teratogenicity in pregnant women.

Administration, Oral↗
PubMed2005

Exposure to retinoic acids in non-pregnant women following high vitamin A intake with a liver meal.

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

Adolescent↗
PubMed2005

Polyphenols and glutathione synthesis regulation.

Polyphenols in food plants are a versatile group of phytochemicals with many potentially beneficial activities in terms of disease prevention. In vitro cell culture experiments have shown that polyphenols possess antioxidant properties, and it is thought that these activities account for disease-preventing effects of diets high in polyphenols. However, polyphenols may be regarded as xenobiotics by animal cells and are to some extent treated as such, ie, they interact with phase I and phase II enzyme systems. We recently showed that dietary plant polyphenols, namely, the flavonoids, modulate expression of an important enzyme in both cellular antioxidant defenses and detoxification of xenobiotics, ie, gamma-glutamylcysteine synthetase. This enzyme is rate limiting in the synthesis of the most important endogenous antioxidant in cells, glutathione. We showed in vitro that flavonoids increase expression of gamma-glutamylcysteine synthetase and, by using a unique transgenic reporter mouse strain, we showed increased expression in vivo, with a concomitant increase in the intracellular glutathione concentrations in muscles. Because glutathione is important in redox regulation of transcription factors and enzymes for signal transduction, our results suggest that polyphenol-mediated regulation of glutathione alters cellular processes. Evidently, glutathione is important in many diseases, and regulation of intracellular glutathione concentrations may be one mechanism by which diet influences disease development. The aim of this review is to discuss some of the mechanisms involved in the glutathione-mediated, endogenous, cellular antioxidant defense system, how its possible modulation by dietary polyphenols such as flavonoids may influence disease development, and how it can be studied with in vivo imaging.

Animals↗
PubMed2005

Dietary antioxidants and cardiovascular disease.

PURPOSE OF REVIEW: Oxidative damage is involved in cardiovascular diseases. Intervention with alpha-tocopherol, ascorbic acid and beta-carotene does not appear to reduce pathogenesis. The purpose of this review is to describe alternative antioxidant mechanisms that may be involved. RECENT FINDINGS: Antioxidants with different chemical properties may recharge each other in an antioxidant network. The total antioxidant content of dietary plants may therefore be a useful tool for testing the "antioxidant network" hypothesis. Several berries, fruits, nuts, seeds, vegetables, drinks and spices have been found to be high in total antioxidants. Initial studies in animals and humans are supportive as to the beneficial effects of dietary plants rich in total antioxidants. Additionally, antioxidants and other plant compounds may also improve the endogenous antioxidant defence through induction of antioxidant and phase 2 enzymes. Dietary plants rich in such compounds include broccoli, Brussels sprouts, cabbage, kale, cauliflower, carrots, onions, tomatoes, spinach and garlic. SUMMARY: Although initial studies have indicated that antioxidants may reduce oxidative stress, human intervention studies do not support a beneficial effect of antioxidant supplements. Further research is needed to clarify whether other plant antioxidants, plants rich in a combination of antioxidants, or plant compounds that induce the endogenous antioxidant defence can reduce pathogenesis of cardiovascular disease and other oxidative stress-related diseases.

Animals↗
PubMed2004

Molecular imaging of the transcription factor NF-kappaB, a primary regulator of stress response.

A wide range of environmental stress and human disorders involves inappropriate regulation of NF-kappaB, including cancers and numerous inflammatory conditions. We have developed transgenic mice that express luciferase under the control of NF-kappaB, enabling real-time non-invasive imaging of NF-kappaB activity in intact animals. We show that, in the absence of stimulation, strong, intrinsic luminescence is evident in lymph nodes in the neck region, thymus, and Peyer's patches. Treating mice with stressors, such as TNF-alpha, IL-1alpha, or lipopolysaccharide (LPS) increases the luminescence in a tissue-specific manner, with the strongest activity observable in the skin, lungs, spleen, Peyer's patches, and the wall of the small intestine. Liver, kidney, heart, muscle, and adipose tissue exhibit less intense activities. Exposure of the skin to a low dose of UV-B radiation increases luminescence in the exposed areas. In ocular experiments, LPS- and TNF-alpha injected NF-kappaB-luciferase transgenic mice exhibit a 20-40-fold increase in lens NF-kappaB activity, similar to other LPS- and TNF-alpha-responsive organs. Peak NF-kappaB activity occurs 6h after injection of TNF-alpha and 12h after injection of LPS. Peak activities occur, respectively, 3 and 6h later than that in other tissues. Mice exposed to 360J/m(2) of UV-B exhibit a 16-fold increase in NF-kappaB activity 6h after exposure, characteristically similar to TNF-alpha-exposed mice. Thus, in NF-kappaB-luciferase transgenic mice, NF-kappaB activity also occurs in lens epithelial tissue and is activated when the intact mouse is exposed to classical stressors. Furthermore, as revealed by real-time non-invasive imaging, induction of chronic inflammation resembling rheumatoid arthritis produces strong NF-kappaB activity in the affected joints. Finally, we have used the model to demonstrate NF-kappaB regulation by manipulating the Vitamin A status in mice. NF-kappaB activity is elevated in mice fed a Vitamin A deficient (VAD) diet, and suppressed by surplus doses of retinoic acid (RA). We thus demonstrate the development and use of a versatile model for monitoring NF-kappaB activation both in tissue homogenates and in intact animals after the use of classical activators, during disease progression and after dietary intervention.

Animals↗
PubMed2004

[Antioxidants and oxidative stress].

BACKGROUND: Oxidative damage is related to the development of several diseases. An improved antioxidant defence may therefore protect against these diseases. Recent studies have demonstrated that dietary plants contain several hundred different antioxidants. MATERIALS AND METHODS: We have systematically assessed the total amount of antioxidants in a variety of dietary plants by the "ferric-reducing ability of plasma" assay, a method that measures the sum total of all antioxidants above a reference redox potential. RESULTS: Our results demonstrate that antioxidant levels vary considerably. Plants with the highest values include dog rose, sour cherry, blackberry, crowberry, blueberry, walnuts, sunflower seed, pomegranate and ginger. Among the dried culinary herbs tested, we found very high levels of antioxidants in oregano, sage, peppermint, garden thyme, lemon balm, clove, allspice and cinnamon. INTERPRETATION: Our results are in accordance with studies in experimental animals demonstrating beneficial effect against age-related neurodegeneration, carcinogenesis and atherosclerosis after treatment with some of the most antioxidant-rich foods identified in the present study.

Animals↗
PubMed2004

[Biological effects of vitamin K and concentration of vitamin K in Norwegian food].

BACKGROUND: Vitamin K has several biological effects and dietary intake seems to be more important than previously believed because of low bioavailability of the vitamins from the colon. MATERIALS AND METHODS: Data from the literature were identified on PubMed, and data from NORKOST II (a dietary study from 1997 based on a nation-wide sample of respondents) were used to calculate dietary intake of vitamin K. RESULTS: The dietary intake of vitamin K in Norway seems to be < 50% of what is recommended. The stores of vitamin K are small and T/2 in the body is approximately 1-1.5 day. Vitamin K executes its effects by carboxylation of proteins and as ligand (vitamin K2) for a nuclear transcription factor. Biological effects beyond coagulation include bone formation, neural functioning and blood vessel calcification. Anticoagulation with warfarin inhibits vitamin K-dependent reactions and may have detrimental effects on bone formation. INTERPRETATION: It is possible that the high incidence of osteoporosis in Norway may be due to the low dietary intake of vitamin K, hence it is suggested that the intake of vitamin K should be increased and vitamin K antagonists be replaced with specific thrombin inhibitors. New technology allows measurements of plasma concentration of vitamin K in relation to malabsorption, insufficient diet, and osteoporosis.

Adult↗
PubMed2004

Vitamin A status significantly alters nuclear factor-kappaB activity assessed by in vivo imaging.

Our study aimed to investigate, in vivo, the relationship between vitamin A status and NF-kappaB activity, a transcription factor central in regulating inflammatory and immune responses. We used a novel transgenic murine NF-kappaB-luciferase reporter model that enabled molecular imaging of NF-kappaB activity in live mice via an intensified image-capture apparatus. Whole-body luminescence, which reflects overall NF-kappaB activity, was elevated 2.2-fold in vitamin A-deficient (VAD) mice compared with control mice. Specifically, NF-kappaB activity in VAD mice was increased 1.8-fold in the lymph nodes and 1.4-fold in the thymus and, NF-kappaB induction in UVB radiation-exposed skin was also enhanced in VAD mice compared with control mice. The administration of all-trans retinoic acid to VAD mice resulted in a transient reduction in NF-kappaB activity and, conversely, a single dose of the RAR-pan-antagonist, AGN 194310, administered to control mice, led to a marked, transient induction of whole-body luminescence. Our results suggest that vitamin A status, and vitamin A itself, affects NF-kappaB activity in vivo and that the elevated NF-kappaB activity in VAD may be a mechanism underlying some of the features of VAD syndrome.

Animals↗
PubMed2004

Flagellin promotes myeloid differentiation factor 88-dependent development of Th2-type response.

Activation of dendritic cells (DC) by microbial products via Toll-like receptors (TLR) is instrumental in the induction of immunity. In particular, TLR signaling plays a major role in the instruction of Th1 responses. The development of Th2 responses has been proposed to be independent of the adapter molecule myeloid differentiation factor 88 (MyD88) involved in signal transduction by TLRs. In this study we show that flagellin, the bacterial stimulus for TLR5, drives MyD88-dependent Th2-type immunity in mice. Flagellin promotes the secretion of IL-4 and IL-13 by Ag-specific CD4(+) T cells as well as IgG1 responses. The Th2-biased responses are associated with the maturation of DCs, which are shown to express TLR5. Flagellin-mediated DC activation requires MyD88 and induces NF-kappaB-dependent transcription and the production of low levels of proinflammatory cytokines. In addition, the flagellin-specific response is characterized by the lack of secretion of the Th1-promoting cytokine IL-12 p70. In conclusion, this study suggests that flagellin and, more generally, TLR ligands can control Th2 responses in a MyD88-dependent manner.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Intralobular Distribution of Vitamin A-Storing Lipid Droplets in Hepatic Stellate Cells with Special Reference to Polar Bear and Arctic Fox.

We examined the liver of adult polar bears, arctic foxes, and rats by gold chloride staining, fluorescence microscopy for the detection of autofluorescence of vitamin A, hematoxylin-eosin staining, staining with Masson's trichrome, Ishii and Ishii's silver impregnation, and transmission electron microscopical morphometry. The liver lobules of the arctic animals showed a zonal gradient in the storage of vitamin A. The density (i.e., cell number per area) of hepatic stellate cells was essentially the same among the zones. These results indicate that the hepatic stellate cells of the polar bears and arctic foxes possess heterogeneity of vitamin A-storing capacity in their liver lobules.

Journal Article↗
PubMed2004

Vitamin A distribution and content in tissues of the lamprey, Lampetra japonica.

Vitamin A (retinol and retinyl ester) distribution and content in tissues of a lamprey (Lampetra japonica) were analyzed by morphological methods, namely, gold chloride staining, fluorescence microscopy to detect specific vitamin A autofluorescence, and electron microscopy, as well as high-performance liquid chromatography (HPLC). Hepatic stellate cells showed an abundance of vitamin A stored in lipid droplets in their cytoplasm. Similar cells storing vitamin A were present in the intestine, kidney, gill, and heart in both female and male lampreys. Morphological data obtained by gold chloride staining method, fluorescence microscopy, transmission electron microscopy, and HPLC quantification of retinol were consistent. The highest level of total retinol measured by HPLC was found in the intestine. The second and third highest concentrations of vitamin A were found in the liver and the kidney, respectively. These vitamin A-storing cells were not epithelial cells, but mesoderm-derived cells. We propose as a hypothesis that these cells belong to the stellate cell system (family) that stores vitamin A and regulates homeostasis of the vitamin in the whole body in the lamprey. Fibroblastic cells in the skin and somatic muscle stored little vitamin A. These results indicate that there is difference in the vitamin A-storing capacity between the splanchnic and intermediate mesoderm-derived cells (stellate cells) and somatic and dorsal mesoderm-derived cells (fibroblasts) in the lamprey. Stellate cells derived from the splanchnic and intermediate mesoderm have high capacity and fibroblasts derived from the somatic and dorsal mesoderm have low capacity for the storage of vitamin A in the lamprey.

Animals↗
PubMed2004

Molecular imaging of the biological effects of quercetin and quercetin-rich foods.

The human diet contains several thousands of organic plant molecules (i.e. phytochemicals), many of which have significant bioactivities. The specific physiological effects of these compounds are impossible to predict from in vitro studies using cell cultures and cell-free model systems. Nutrigenomics, which may be defined as the application of genomic tools to study the integrated effects of nutrients on gene regulation, however, holds great promise in increasing the understanding of how nutrients affect molecular events in an organism. Quercetin, a phytochemical belonging to the flavonoids, has antioxidant activities, inhibit protein kinases, inhibit DNA topoisomerases and regulate gene expression. The aim of the present review is to describe some of the many effects of quercetin, and how molecular imaging using transgenic reporter mice may serve as a tool to study the integrated influence of quercetin and other dietary phytochemicals on gene expression in vivo. We are using the bioluminescence emitted from firefly luciferase as the reporter since light originating from the inside of a cell or organism can be detected externally in an intact living organism. Molecular imaging using reporter models is therefore a unique technology to study the integrated effects of environmental insults and dietary substances on the influence of gene expression in disease development. We utilize these in vivo models to elucidate the role of various flavonoids, such as quercetin, for modulating gene expression related to oxidative stress and the antioxidant defence system.

Animals↗
PubMed2004

Is serum gamma glutamyltransferase a marker of oxidative stress?

The primary role of cellular gamma glutamyltransferase (GGT) is to metabolize extracellular reduced glutathione (GSH), allowing for precursor amino acids to be assimilated and reutilized for intracellular GSH synthesis. Paradoxically, recent experimental studies indicate that cellular GGT may also be involved in the generation of reactive oxygen species in the presence of iron or other transition metals. Although the relationship between cellular GGT and serum GGT is not known and serum GGT activity has been commonly used as a marker for excessive alcohol consumption or liver diseases, our series of epidemiological studies consistently suggest that serum GGT within its normal range might be an early and sensitive enzyme related to oxidative stress. For example, serum and dietary antioxidant vitamins had inverse, dose-response relations to serum GGT level within its normal range, whereas dietary heme iron was positively related to serum GGT level. More importantly, serum GGT level within its normal range positively predicted F2-isoprostanes, an oxidative damage product of arachidonic acid, and fibrinogen and C-reactive protein, markers of inflammation, which were measured 5 or 15 years later, in dose-response manners. These findings suggest that strong associations of serum GGT with many cardiovascular risk factors and/or events might be explained by a mechanism related to oxidative stress. Even though studies on serum and/or cellular GGT is at a beginning stage, our epidemiological findings suggest that serum GGT might be useful in studying oxidative stress-related issues in both epidemiological and clinical settings.

Biomarkers↗
PubMed2004

Intakes of antioxidants in coffee, wine, and vegetables are correlated with plasma carotenoids in humans.

The consumption of fruits and vegetables reduces the risk of major chronic degenerative diseases. The active compounds and the mechanisms involved in this protective effect have not been well defined. The objective of this study was to determine the contribution of various food groups to total antioxidant intake, and to assess the correlations of the total antioxidant intake from various food groups with plasma antioxidants. We collected 7-d weighed dietary records in a group of 61 adults with corresponding plasma samples, and used data from a nationwide survey of 2672 Norwegian adults based on an extensive FFQ. The total intake of antioxidants was approximately 17 mmol/d with beta-carotene, alpha-tocopherol, and vitamin C contributing <10%. The intake of coffee contributed approximately 11.1 mmol, followed by fruits (1.8 mmol), tea (1.4 mmol), wine (0.8 mmol), cereals (i.e., all grain containing foods; 0.8 mmol), and vegetables (0.4 mmol). The intake of total antioxidants was significantly correlated with plasma lutein, zeaxanthin, and lycopene. Among individual food groups, coffee, wine, and vegetables were significantly correlated with dietary zeaxanthin, beta-carotene, and alpha-carotene. These data agree with the hypothesis that dietary antioxidants other than the well-known antioxidants contribute to our antioxidant defense. Surprisingly, the single greatest contributor to the total antioxidant intake was coffee.

Adult↗
PubMed2003

Capillary high-performance liquid chromatographic determination of lutein and zeaxanthin in aqueous humor from a single mouse eye.

To protect the eye from ultraviolet phototoxicity caused by free radicals, ocular components such as the aqueous humor accumulate antioxidants, such as the carotenoids. Lutein and zeaxanthin are the only carotenoids known to be present in the aqueous humor. Due to the small sample volume, pooling of samples from an undesirable large number of animals is often required for sufficient sensitivity and statistically significant differences to be achieved. In this paper we present a rapid, sensitive and robust packed capillary high-performance liquid chromatographic visible detection method for the quantification of lutein and zeaxanthin in the aqueous humor of single mouse eyes.

Animals↗
PubMed2003

Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations.

BACKGROUND: It is well established that an excessive intake of retinol (vitamin A) is toxic; however, it has been > 25 y since the last extensive treatise of case reports on this subject. OBJECTIVE: The objectives were to identify and evaluate all individual cases of retinol toxicity published in the scientific literature that assessed the thresholds and symptoms induced by high intakes of retinol and to compare the toxicity of different physical forms of retinol preparations. DESIGN: We performed a meta-analysis of case reports on toxicity claimed to be induced by intakes of excessive amounts of dietary retinol (ie, retinol and retinyl esters in foods or supplements). Using free text and MESH (medical subheading) strategies in PubMed, we identified 248 articles in the scientific literature. From these initial articles we identified other relevant citations. The final database consisted of 259 cases in which individual data on dose, sex, age, time of exposure, and symptoms are reported. RESULTS: Chronic hypervitaminosis A is induced after daily doses of 2 mg retinol/kg in oil-based preparations for many months or years. In contrast, doses as low as 0.2 mg retinol. kg(-1). d(-1) in water-miscible, emulsified, and solid preparations for only a few weeks caused chronic hypervitaminosis A. Thus, water-miscible, emulsified, and solid preparations of retinol are approximately 10 times as toxic as are oil-based retinol preparations. The safe upper single dose of retinol in oil or liver seems to be approximately 4-6 mg/kg body wt. These thresholds do not vary considerably with age. CONCLUSIONS: The results of the present study indicate that the physical form of retinol supplements is a major determinant of toxicity. The use of water-miscible, emulsified, and solid preparations of retinol should therefore be carefully considered before being used in supplements and fortifications.

Adolescent↗