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Summary
Oxidant stress - i.e. the prevalence within the cell of oxidizing species over the cellular antioxidant potential - is recognized as a primary factor in the pathogenesis of a series of important human pathologies. The possibility of a preventive or therapeutic intervention by means of antioxidant factors, including those naturally contained in diet, increases the importance of a correct understanding of the molecular mechanisms involved in such pathologies. A number of sophisticated biochemical methods are available, for the monitoring of nearly all oxidant stress-related processes; their applicability to in vivo conditions is however limited. In these conditions, the histochemical visualization in tissue sections and isolated cells of selected molecular markers for oxidative phenomena can often provide valuable information about the distribution of processes in vivo. This paper includes an overview of the basic biochemical reactions occurring during oxidant stress and lipid peroxidation, as well as of the main histochemical studies published in the field.
Keywords
Oxidant stress, Lipid peroxidation, Histochemistry, Confocal microscopy, Image analysis
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Involvement of oxygen free radicals in ischemia-/reperfusion injury is based on measurement of increased products of lipid peroxidation after organ ischemia and restoration of blood flow during surgical operations and reperfusion of organ transplants. In cardiology inverse epidemiological correlations between plasma vitamin E levels and mortality due to ischemic heart disease, as well as beneficial effects of vitamin E on experimentally induced oxidative damage to the heart support the hypothesis, that vitamin E might have a protective role against myocardial ischemia-/reperfusion injury. In abdominal surgery efficiency of free radical scavengers has been intensively studied on animal models of hepatic ischemia and reperfusion. Examination of free radical scavengers and adenosine metabolites in liver tissue during hepatic ischemia revealed that vitamin E and glutathione levels as well as hepatic adenosine triphosphate levels are decreased during hepatic ischemia and reperfusion. The beneficial effects of a-tocopherol on hepatic viability and survival rate after ischemia and reperfusion demonstrated in these studies will be of great importance concerning further studies in organ preservation. In clinical kidney transplantation prevention of lipid peroxidation and improvement in kidney viability and function was demonstrated after infusion of a multivitamin cocktail in a prospective randomised study.
Keywords
Ischemia-/reperfusion injury, Antioxidants, Myocardial ischemia, Hepatic ischemia, Intestinal ischemia, Vitamin A, beta-Carotene, Vitamin E, Vitamin C, Animal models
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
An adequate host defense activity critically depends upon the
micronutrient status of an individual among which the cellular
oxidant-antioxidant balance is an important determinant. Oxidative
burst is part of the physiological function of phagocytes connected
to a massive production and release of reactive oxygen intermediates.
At the same time, maintenance of the functional capacity of the host
defense system in fighting against microorganisms and foreign
antigens is significantly affected by the various reactive oxygen
species. In order to compensate for this critical condition
phagocytes do show active uptake and physiologically high
intracellular concentrations of antioxidants.
Thus, optimal function of the host defense system depends upon an
adequate supply of antioxidative micronutrients and, on the other
hand, impaired host defense activity can act as a very early and
sensitive marker of marginal deficiency of antioxidant
micronutrients. Assessment of immune functions can serve as an
important preventative diagnostic tool in the detection of marginal
but functionally relevant micronutrient deficiencies. Intervention
into the functionally deficient antioxidant micronutrient status can
act as the appropriate preventative or therapeutic treatment with
higher efficacy and less adverse effects than direct pharmacological
modulation of single immune functions by specific mediators.
Keywords
Immune response, Antioxidants, Phagocytes, Antibodies, Disease prevention
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Infection and trauma cause inflammatory stress in patients. Tissue damage, enhanced inflammatory mediator production and suppressed lymphocyte function may occur as a consequence. The antioxidative vitamins, ascorbic acid and the tocopherols, are important not only for limiting tissue damage but also in preventing increased cytokine production which is a consequence of excessive activation of NFkB. Glutathione is a major endogenous antioxidant and is important for lymphocyte replication. Two vitamins, vitamin B6 and riboflavin participate in the maintainance of glutathione status. The former vitamin acts as a cofactor in the synthesis of cysteine (the rate limiting precursor for glutathione biosynthesis) and the latter vitamin is a cofactor for glutathione reductase. Deficiencies in tocopherol, vitamin B6 and riboflavin reduce cell numbers in lymphoid tissues of experimental animals and produce functional abnormalities in the cell mediated immune response. Ascorbic acid and tocopherols exert anti-inflammatory effects in studies in man and animals. In humans, dietary supplementation with ascorbic acid, tocopherols and vitamin B6 enhances a number of aspects of lymphocyte function. The effect is most apparent in the elderly.
Keywords
Vitamins, Antioxidants, NFkB, Cytokines, Immune function
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Postnatally a rapid change occurs from a relatively hypoxic to a relatively hyperoxic environment, especially during artificial ventilation with all risks of ROS-formation. Among the non enzymatic antioxidative strategies the vitamins E, C, A and B2 are of major importance. Vitamin E is considered the most important radical scavenging vitamin of the lipid soluble compartment. Hereby vitamin E itself is converted into a radical which is handed over to vitamin C and glutathione into the water soluble compartment. The vitamin E content of the fetus increases with the fetal fat mass mainly during the last trimester of pregnancy. Placenta is only slightly permeable to lipid soluble vitamins. Vitamin E deficiency may rapidly develop typically at about 6p;8 weeks of age. Vitamin E is able to prolong significantly the onset of retinopathic changes during oxygen therapy and may prevent intraventricular hemorrhage. Vitamin C is together with glutathione a major representative of the non enzymatic antioxidative system in the water soluble compartment. The best determinant of the vitamin C status is its concentration in leukocytes. Vitamin C reduces iron to the divalent state which supports the hydroxyl radical formation (Haber-Weiss reaction). This should be considered mainly in cases of intraventricular hemorrhage. Vitamin B2 acts mainly as cofactor of glutathione reductase which keeps glutathione in the reduced state. It can therefore be considered an indirect antioxidative vitamin. Vitamin B2 is destroyed by light. Phototherapy has been recognized as a cause of riboflavin deficiency. Vitamin A comprises all retinols with properties like trans-retinol. Reti-nol storage in the fetal liver increases during late pregnancy. In both, premature and mature newborns, the serum concentrations amount to only about 50% of those of their mothers. Vitamin A has a paramount importance for fetal lung development, because the individual surfactant proteins are selectively regulated by retinoic acid.
Keywords
Newborns, Vitamin E, Vitamin C, Vitamin B2, Transition metals
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
In 1970 Linus Pauling claimed that vitamin C prevents and alleviates the episodes of the common cold. Pauling was correct in concluding from trials published up till then, that in general vitamin C does have biological effects on the common cold, but he was rather over-optimistic as regards the size of benefit. His quantitative conclusions were based on a single placebo-controlled trial on schoolchildren in a skiing camp in the Swiss Alps, in which a significant decrease in common cold incidence and duration in the group administered 1 g/day of vitamin C was found. As children in a skiing camp are not a representative sample of the general population, Pauling's extrapolation to the population at large was too bold, erring as to the magnitude of the effect. Nevertheless, Pauling's general conclusion that vitamin C has physiological effects on the common cold is of major importance as it conflicts with the prevailing consensus that the only physiological effect of vitamin C on human beings is to prevent scurvy.
Keywords
Ascorbic acid, Upper respiratory infections, Controlled trials, Children
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Reactive oxygen intermediates (ROIs) are an evolutionarily ancient threat to all organisms. Both prokaryotic and higher eukaryotic cells are able to alter their genetic program in response to changes in the intracellular levels of ROIs. In bacteria and yeast, this response leads to the new synthesis of proteins that protect cells from the consequences of oxidative damage, such as DNA strand breaks, lipid peroxidation and oxidative damage of proteins. Intriguingly, higher organisms have also evolved cellular mechanisms to actively produce ROIs. There is increasing evidence that ROIs fulfil an important role as second messengers involved in signal transduction. We have proposed that ROIs have been conserved throughout evolution as universal pathogen messengers turning on genes with important functions in the immune response and cell proliferation. The higher eukaryotic transcription factors NF-kB and AP-1 will be described as proteins which are regulated by ROIs under a great variety of pathogenic conditions and initiate the new expression of genes with important roles in immune, inflammatory and other pathogen-related genetic responses.
Keywords
AP-1, NF-kB, Reactive oxygen intermediates, Signal transduction, Transcription factors
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
a-Tocopherol but not b-tocopherol, activates protein phosphatase 2A, decreases protein kinase C activity and attenuates smooth muscle cell proliferation at physiological concentrations. b-Tocopherol prevents the effects of a-tocopherol. Inhibition of protein kinase Ca, but not of the other isoforms, by the inhibitor Gö6976 prevents the effect of a-tocopherol. Protein kinase Ca, immunoprecipitated from a-tocopherol treated cells, is less phosphorylated and inactive. It is proposed that the specific activation of protein phosphatase 2A by a-tocopherol results in dephosphorylation and inactivation of protein kinase Ca. Finally, this cascade of events leads to smooth muscle cell proliferation inhibition.
Keywords
a-Tocopherol, Vitamin E, Protein kinase C, Vascular smooth muscle cell, Cell proliferation, Protein phosphatase, Oxidative stress
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Vitamin K is required for the biological activity of several coagulation factors, which is considered as the classical function of vitamin K. Recent research, however, suggests a role of vitamin K in bone metabolism. The metabolic role of vitamin K is to facilitate the carboxylation of glutamyl to g-carboxyglutamyl residues. Besides the hepatic tissue, in which the clotting factors are produced g-carboxyglutamyl-containing proteins are also abundantly available in bone tissue. Osteocalcin accounts for up to 80% of the total g-carboxyglutamyl content of mature bone. Human carboxylated osteocalcin contains 3 g-carboxyglutamyl residues which confer a highly specific affinity to the calcium ion of the hydroxyapatite molecule. Besides the g-carboxylation of osteocalcin vitamin K may also affect other parameters of bone metabolism, such as calcium hemostasis, and prostaglandin E2 and interleukin 6 production. Evidence from observational studies and first intervention trials indicate that vitamin K intakes much higher than the current recommendations improved biochemical markers of bone formation as well as bone density. In conclusion, the mechanistic data as well as the observational data and the results of the first controlled clinical trials in humans point to a beneficial effect of additional intakes of vitamin K in bone health.
Keywords
Vitamin K, Osteocalcin, Osteoporosis, Epidemiology, Intervention, Calcium, Requirements
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
We compared the ability of all-trans-retinoic acid (RA), all-trans-retinoyl-beta-D-glucuronide (RAGL), and all-trans-beta-carotene (BC) to inhibit growth and to induce differentiation of the human promyelocytic leukemia cell line HL-60 into morphologically mature granulocytes. BC was made water-soluble by the solutol-solvent-system. RA (1 mM) could induce differentiation of 85% of the HL-60 cells after a total incubation time of 180 hours, RAGL (5 mM) induced 64% of the cells, whereas 33% of the HL-60 cells were differentiated after incubation with BC (10 mM), which was determined by assessing cell functional capacity to reduce nitroblue tetrazolium dye in response to phorbolesters. The absence of RA in RAG and BC treated cells gives strong evidence that RAG and BC exert intrinsic biological effects.
Keywords
Retinoids, Carotene-retinoyl-glucuronides, Differentiation-HL-60, Chemiluminescence
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Stimulation of gap junctional communication has been suggested to be one of the biochemical mechanisms underlying the cancer-preventive activity of carotenoids. The stimulatory activity is associated with structural properties of the carotenoids. It appears that the presence of a six-membered ring substituent at the end of the conjugated system of double bonds is required for the effects; five-membered ring carotenoids are less active. There is increasing evidence that oxidation products of carotenoids, especially retinoic acid analogs, significantly contribute to this biological property.
Keywords
Carotenoids, Structure, Gap junctions, Intercellular communication, Connexin, Retinoids, 4-oxo-Retinoic acid
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
In a clinical trial the effect of chemoprevention with beta-carotene, vitamin E and C on dysplastic tissue was studied. The study included 24 patients with oral leukoplakia and 24 patients after radical resection of a primary oral cancer. There was a reduction of increased cell kinetic parameters like the S-phase portion or the average number of nuclear-organizer regions (NOR) per cell nucleus, a decrease of the micronuclei portion and a normalization of the cytokeratin gene-expression. The general response was 97.5%. Stopping the alcohol and tobacco abuse the effect of the antioxidative vitamins on redifferentiation of the oral mucosa was more intense than by persistance of the alcohol and tobacco abuse, but a long term prevention seems to be ineffective.
Keywords
Chemoprevention, Beta-carotene, a-Tocopherol, Oral dysplasia. Vitamin C, Antioxidant, Oxygen radicals
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Acquired biotin deficiency and the two known congenital disorders of biotin metabolism, biotinidase and holocarboxylase synthetase (HCS) deficiency, all lead to deficiency of the 4 biotin-dependent carboxylases, i.e. to multiple carboxylase deficiency (MCD). The underlying mechanism in HCS-deficiency, discovered in 1981, is decreased affinity of HCS for biotin impairing the formation of holocarboxylases at physiological biotin levels. In biotinidase deficiency, discovered in 1983, MCD results from progressive development of biotin-deficiency due to inability to liberate and recycle biotin which is lost in urine as biocytin. MCD leads to typical organic aciduria and severe life-threatening illness. Main symptoms and signs are feeding difficulties, neurologic abnormalities (hypotonia, impaired consciousness, seizures, atax-ia) and cutaneous changes (rash, alopecia). However, the clinical presentation and age of onset are extremely variable, and organic aciduria may initially be absent in biotinidase deficiency. Therefore, the definitive diagnosis requires enzyme studies. MCD can be detected in lymphocytes obtained before treatment and biotinidase deficiency is confirmed or excluded by a colorimetric enzyme assay in plasma. Newborn screening for biotinidase deficiency has resulted in the detection of patients with partial deficiency (10 - 30% of mean normal activity) in addition to patients with profound deficiency (0 - 10%). Severe illness has been observed mainly in patients with 0-activity or a Km-mutation, detection of which requires detailed investigation. HCS-deficiency has to be confirmed by enzyme assay in cultured cells. Both congenital disorders respond clinically and biochemically to oral biotin therapy. Whereas 10 mg/day or less is sufficient to treat profound biotinidase deficiency, the optimal biotin dose for patients with HCS-deficiency must be assessed individually. The prognosis of both disorders is good if biotin therapy is introduced early and continued throughout life. However, delayed commencement of therapy in biotinidase deficiency can result in irreversible neurological damage, and in HCS-deficiency a few patients have responded only partially even to massive biotin doses of up to 100 mg/day.
Keywords
Biotin, Biotin deficiency, Biotin therapy, Biotinidase deficiency, Holocarboxylase synthetase deficiency, Multiple carboxylase deficiency, Organic aciduria, Inborn error of metabolism
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern
Summary
Increased plasma concentrations of the sulfur-containing amino acid homocyst(e)ine are designated as hyperhomocyst(e)inemia. Various definitions have been used to derive cutoff levels for hyperhomocyst(e)inemia. The classification by Kang is now generally used distinguishing moderate, intermediate and severe hyperhomocyst(e)inemia. A variety of causes are discussed for the etiology of the disease which can be grouped into genetic and nongenetic factors. Severe hyperhomocyst(e)inemia is accompanied by homocystinuria and several other symptoms occurring early in life. Treatment is mandatory for normal development and prevention of premature atherosclerosis. Even less severe forms of hyperhomocyst(e)inemia imply a substantially elevated risk for vascular diseases. Etiology and severity of defect(s) leading to hyperhomocyst(e)inemia are the basis for treatment. In genetic defects, supplementation with the cofactor(s) of the affected enzyme is used to enhance enzyme activity. Alternative routes in the pathway may also be enhanced. Nongenetic hyperhomocyst(e)inemia often requires correction of suboptimal vitamin concentrations. Nutritive doses of the vitamins may be sufficient for treatment of less severe forms as well as for prevention of hyperhomocyst(e)inemia.
Keywords
Homocyst(e)ine, Hyperhomocyst(e)inemia, Classification, Etiology, Prevalence
International Journal for Vitamin and Nutrition Research,
Band 67, 1997, Heft 5, © Verlag Hans Huber, Bern