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Biomedical subjects

L G Korkina

Publications and source records attributed to L G Korkina.

At least 19 recordsLinked to original sources
PubMed2001

Enhancement of antioxidant and anti-inflammatory activities of bioflavonoid rutin by complexation with transition metals.

The antioxidant and anti-inflammatory activities of two transition metal complexes of bioflavonoid rutin, Fe(rut)Cl(3) and Cu(rut)Cl(2), were studied. It was found that Cu(rut)Cl(2) was a highly efficient in vitro and ex vivo free radical scavenger that sharply decreased (by 2-30 times compared to the parent rutin): oxygen radical production by xanthine oxidase, rat liver microsomes, and rat peritoneal macrophages; the formation of thiobarbituric acid-reactive products in microsomal lipid peroxidation; and the generation of oxygen radicals by broncho-alveolar cells from bleomycin-treated rats. The copper-rutin complex was also a superior inhibitor of inflammatory and fibrotic processes (characterized by such parameters as macrophage/neutrophil ratio, wet lung weight, total protein content, and hydroxyproline concentration) in the bleomycin-treated rats. The antioxidant activity of Fe(rut)Cl(3) was much lower and in some cases approached that of rutin. Fe(rut)Cl(3) also stimulated to some degree spontaneous oxygen radical production by macrophages. We suggested that the superior antioxidant and anti-inflammatory activity of the copper-rutin complex is a consequence of its acquiring the additional superoxide-dismuting copper center. The inhibitory activity of Fe(rut)Cl(3) was lower, probably due to the partial reduction into Fe(rut)Cl(2) in the presence of biological reductants; however, similarly to the copper-rutin complex, this complex efficiently suppressed lung edema.

Animals↗
PubMed2001

The role of oxidative stress in developmental and reproductive toxicity of tamoxifen.

The antiestrogen tamoxifen (TAM) is widely used as a drug against breast cancer and is currently being tested as a chemopreventive agent. However, a number of studies showed genotoxic and carcinogenic effects of TAM. These effects are thought to be related to oxygen radical overproduction which occurs during TAM metabolic activation. There is no evidence, thus far, on TAM toxicity to embryos and gametes. The present study was designed to elucidate the mechanisms of TAM-induced developmental, reproductive and cytogenetic toxicity towards sea urchin (SU) embryos with regard to the possibility of TAM-initiated oxidative stress. Embryo cultures from SU were subjected to long-term (throughout embryogenesis) or short-term (two hours) incubation with TAM at concentrations from 10(-8) to 10(-5) M. The experiments on TAM-induced toxicity to gametes were carried out with SU sperm, or unfertilized eggs, suspended in TAM (10(-8) to 10(-6) M). To assess the effects of TAM to embryos or to gametes, developmental defects, embryonic mortality, fertilization success, and cytogenetic abnormalities were scored. Oxidative damage to DNA and lipids was detected by measurements of 8OHdG levels and lipid peroxidation, respectively. Reactive oxygen species (ROS) production by eggs and embryos was recorded by luminol-dependent chemiluminescence (LDCL) and cytochrome c reduction methods. The changes in activities of SU superoxide dismutase (SOD) and catalase were also evaluated. TAM exerted: a) early embryonic mortality to exposed embryos and to the offspring of exposed eggs; b) developmental defects to the offspring of exposed sperm; c) decrease in sperm fertilization success, and d) cytogenetic effects in the offspring of exposed sperm or eggs. These morphological effects corresponded to the state of oxidative stress in SU embryos (increased oxidative damage to DNA and lipids and induction of antioxidant enzymes). Since TAM did increase significantly ROS production by embryos, it is suggested that TAM may be metabolically activated by SU embryonic oxidases and peroxidases, which in turn could be induced by TAM. The present study provides further support to the utilization of the SU system as a useful model to help elucidate mechanisms of chemical teratogenesis and carcinogenesis.

Animals↗
PubMed2001

Influence of metal ions on flavonoid protection against asbestos-induced cell injury.

Influence of metal ions (Fe2+, Fe3+, Cu2+, Zn2+) on the protective effect of rutin, dihydroquercetin, and green tea epicatechins against in vitro asbestos-induced cell injury was studied. Metals have been found to increase the capacity of rutin and dihydroquercetin to protect peritoneal macrophages against chrysotile asbestos-induced injury. The data presented here show that this effect is due to the formation of flavonoid metal complexes, which turned out to be more effective radical scavengers than uncomplexed flavonoids. At the same time epicatechins and their metal complexes have similar antiradical properties and protective capacities against the asbestos induced injury of macrophages. Metal complexes of all flavonoids were found to be considerably more potent than parent flavonoids in protecting red blood cells against asbestos-induced injury. It was also found that the metal complexes of all flavonoids were absorbed by chrysotile asbestos fibers considerably better than uncomplexed compounds and probably for this reason flavonoid metal complexes have better protective properties against asbestos induced hemolysis. Thus, the results of the present study show that flavonoid metal complexes may be effective therapy for the inflammatory response associated with the inhalation of asbestos fiber. The advantage of their application could be the strong increase in ROS scavenging by flavonoids and finally a better cell protection under the conditions of cellular oxidative stress.

Adsorption↗
PubMed2000

Spectrin changes occur in erythrocytes from patients with Fanconi's anemia and their parents.

Fanconi's anemia (FA) is a clinically and genetically heterogeneous disease which has been hypothesized to be defective in the detoxification of reactive oxygen species. In this work we report the results obtained by morphometric analyses on the red blood cells (RBCs) from FA patients and their parents. We found that a high rate of erythrocytes from both homozygous and heterozygous subjects was significantly altered. RBCs underwent in fact cytoskeleton-dependent modifications, in particular of spectrin molecule, leading to cell shrinking and blebbing. We hypothesize that these changes may be the result of an oxidative imbalance that probably lead to alterations of RBC plasticity- and deformation-associated functions. Moreover, our results also suggest the possibility to identify FA carriers by the existence of RBC abnormalities.

Adolescent↗
PubMed2000

Cytoskeleton alterations of erythrocytes from patients with Fanconi's anemia.

Fanconi's anemia (FA) is a very rare genetically heterogeneous disease which has been hypothesized to be defective in the detoxification of reactive oxygen species. In this work we report the results obtained by morphometric and biochemical analyses on the red blood cells (RBCs) from FA patients. With respect to RBCs from healthy donors the following changes have been detected: (i) a variety of ultrastructural alterations, mainly surface blebbing typical of acanthocytes and stomatocytes; (ii) a significant quantitative increase of these altered forms; (iii) modifications of spectrin cytoskeleton network; (iv) an altered redox balance, e.g. a decreased catalase activity and significant variations in the GSSG/GSH ratio. We hypothesize that remodeling of the redox state occurring in FA patients results in cytoskeleton-associated alterations of red blood cell integrity and function.

Adolescent↗
PubMed2000

Prospects for nutritional interventions in the clinical management of Fanconi anemia.

The evidence associating Fanconi anemia (FA) phenotype to in-vitro and ex-vivo oxidative stress is reviewed. A cancer-prone genetic disease, FA is characterized by delayed bone marrow failure with a progression to aplastic anemia. It is diagnosed by excess chromosomal instability induced by two clastogens, either diepoxybutane (DEB) or mitomycin C (MMC). Clinical symptoms vary in a broad range including a life-threatening hematological impairment, and an extended set of developmental abnormalities, growth retardation and skin pigmentation. Cancer-proneness in FA results in excess incidence of non-lymphoblastic leukemias, and of some defined solid tumors. The relationships of oxidative stress with FA phenotype rely on a consistent body of evidence that includes: (1) excess formation of DNA oxidative damage (both in vitro and in vivo); (2) cellular protection by hypoxia, low molecular-weight antioxidants, antioxidant enzymes, and thioredoxin overexpression; (3) impaired expression and/or activity of antioxidant enzymes, and (4) the redox-dependent action mechanisms of MMC and DEB. This evidence points to a re-appraisal of FA phenotype, suggesting a causative role for oxidative stress in disease progression towards malignancies and/or bone marrow depletion. A well-established literature reporting epidemiological and experimental data provides the nutritional bases for cancer control. Thus, the present state-of-the-art in the related fields of oxidative stress, nutrition, cancer-proneness and FA phenotype, altogether implies the need to undertake the most appropriate efforts to counteract oxidative stress in the clinical management of FA patients.

Anemia, Aplastic↗
PubMed2000

Redox-dependent toxicity of diepoxybutane and mitomycin C in sea urchin embryogenesis.

The effects and mechanisms of action of diepoxybutane (DEB) and mitomycin C (MMC) were investigated on sea urchin embryogenesis, (Sphaerechinus granularis and Paracentrotus lividus). DEB- and MMC-induced toxicity was evaluated by means of selected end-points, including developmental defects, cytogenetic abnormalities and alterations in the redox status [oxygen-dependent toxicity, Mn-superoxide dismutase (MnSOD) and catalase activities and glutathione (GSH) levels]. Both DEB and MMC exhibited developmental toxicity (at concentrations ranging from 3 x 10(-5) to 3 x 10(-4) M and 3 x 10(-6) to 3 x 10(-5) M, respectively) expressed as larval abnormalities, developmental arrest and mortality. The developmental effects of both compounds were significantly affected by oxygen at levels ranging from 5 to 40%. These results confirmed previous evidence for oxygen-dependent MMC toxicity and are the first report of oxygen dependence for DEB toxicity. Both DEB and MMC exerted significant cytogenetic abnormalities, including mitotoxicity and mitotic aberrations, but with different trends between the two chemicals, at the same concentrations as exerted developmental toxicity. The formation of reactive oxygen species was evaluated using: (i) luminol-dependent chemiluminescence (LDCL); (ii) reactions of the main antioxidant systems, such as GSH content and MnSOD and catalase activities. The results point to clear-cut differences in the effects induced by DEB and MMC. Thus, DEB suppressed GSH content within the concentration range 10(-7)-3 x 10(-5) M. The activity of catalase was stimulated at lower DEB levels (10(-7)-10(-6) M) and then decreased at higher DEB concentrations (> or =10(-5) M). Increasing MMC concentrations induced LDCL and MnSOD activity (> or =10(-6) M) greatly and modulated catalase activity (10(-7) - 10(-6) M). GSH levels were unaffected by MMC. The results suggest that oxidative stress contributes to the developmental and genotoxic effects of both toxins studied, although through different mechanisms.

Animals↗
PubMed1999

Lucigenin is a mediator of cytochrome C reduction but not of superoxide production.

The relevance of lucigenin (bis-N-methylacridinium nitrate)-amplified chemiluminescence (CL) as a specific assay for superoxide ion has recently been disputed (S. I. Liochev and I. Fridovich, Arch. Biochem. Biophys. 337, 115-120, 1997). These authors suggested that the redox cycling of lucigenin can lead to the formation of additional amount of superoxide ion. However, thermodynamic consideration shows that the equilibrium for the reaction O*-2 + Luc2+ if O2 + Luc*+ is completely shifted to the right (Keq = 10(6)); therefore, the redox cycling of lucigenin is of no importance. This conclusion is supported by the study of the effects of lucigenin on cytochrome c reduction by xanthine oxidase. It was found that lucigenin did enhance the rate of cytochrome c reduction with xanthine as a substrate, but it did not increase the rate of xanthine oxidation. When NADH was used as a substrate, lucigenin inhibited the SOD-dependent component of cytochrome c reduction and enhanced both the SOD-independent cytochrome c reduction and NADH oxidation, being a sole acceptor of an electron from the enzyme. All these findings indicate the extremely low probability of lucigenin redox cycling. In our opinion, lucigenin-amplified CL remains the most sensitive and highly specific test for superoxide formation in biological systems.

Acridines↗
PubMed1999

Oxidative stress in cancer prone genetic diseases: a review.

A number of congenital conditions include oxidative stress as a phenotypic hallmark, in spite of very distinct genotypic assets. These disorders include some rare chromosomal instability syndromes and two frequent congenital conditions, Down's syndrome and cystic fibrosis. All of these disorders generate severe biomedical and social handicaps in their progression, resulting in neurological symptoms or malformations, early ageing and cancer proneness. The onset of oxidative stress has been related to excess formation or defective detoxification of reactive oxygen species. Investigations conducted so far have focussed on individual disorders and have utilised a range of different methodologies, so leading to a number of unanswered questions regarding the role(s) for oxidative stress in these disorders. Comparative studies are required, based on homogeneous methods, to provide insights into the pathogenesis of each individual condition, which may open up new avenues for studying ageing and cancer.

Chromosome Aberrations↗
PubMed1998

Effect of rutin and its copper complex on superoxide formation and lipid peroxidation in rat liver microsomes.

Two free radical scavengers, bioflavonoid rutin and the copper-rutin complex Cu(Rut)Cl2, inhibited lucigenin-amplified chemiluminescence and lipid peroxidation in rat liver microsomes, Cu(Rut)Cl2 being a 5-9 times more efficient inhibitor than rutin. The enhanced inhibitory activity of Cu(Rut)Cl2 was due to the presence of the additional superoxide-dismutating center (Cu), as follows from the comparison of its effects on microsomal chemiluminescence and cytochrome c reduction by xanthine oxidase. Similar effects of both inhibitors on superoxide production and lipid peroxidation as well as the elevated activity of Cu(Rut)Cl2 indicate an important role of superoxide ion in the initiation of microsomal lipid peroxidation.

Acridines↗
PubMed1998

Congenital disorders sharing oxidative stress and cancer proneness as phenotypic hallmarks: prospects for joint research in pharmacology.

In spite of very distinct genotypic assets, a number of congenital conditions include oxidative stress as a phenotypic hallmark. These disorders include Fanconi's anaemia, ataxia telangiectasia, xeroderma pigmentosum and Bloom's syndrome, as well as two frequent congenital conditions: Down's syndrome and cystic fibrosis. Cancer proneness is a clinical feature shared by these disorders, while other manifestations include early ageing, neurological symptoms or congenital malformations. The onset of oxidative stress has been related to excess formation, or defective detoxification, of reactive oxygen species (ROS). This can arise from either the abnormal expression or inducibility of ROS-detoxifying enzymes, or by defective absorption of nutrient antioxidants. Resulting oxidative injury has been characterized through: (i) DNA, protein or lipid oxidative damage; (ii) excess ROS formation (in vitro and ex vivo); (iii) sensitivity to oxygen-related toxicity; (iv) improvement of cellular defects by either hypoxia or antioxidants; and (v) circumstantial evidence for in vivo oxidative stress (as e.g. clastogenic factors). Investigations conducted so far have been confined to individual disorders. Comparative studies of selected indicators for oxidative stress could provide further insights into the pathogenesis of each individual condition. Such a unified approach may have wide-ranging consequences for studies of ageing and cancer.

Aging↗
PubMed1998

Hemolytic activity of copper sulfate as influenced by epinephrine and chelating thiols.

AIM: To study the effects of epinephrine, homocysteine, and other complexing agents on the cytotoxicity of copper sulfate. METHODS: In vitro suspensions of human red cells incubated with cupric sulfate were used, and hemolysis was determined by extracellular hemoglobin. RESULTS: The hemolytic activity of CuSO4 (0.3 mmol.L-1) was enhanced by the presence of epinephrine and to a lesser extent by homocysteine, whereas D-penicillamine, succimer, and mercaptodextran reduced the copper-induced hemolysis. The latter 3 chelating thiols also reduced the copper-epinephrine-induced hemolysis. The plasma protein ceruloplasmin reduced markedly the copper-epinephrine-induced hemolysis, even upon concentrations < 20% of that of copper. Chromic chloride, as well, acted anti-hemolytically. CONCLUSION: The latter protectors may interact with the production or activity of toxic oxygen, while classical copper chelators sequester cupric ions from interaction with epinephrine or homocysteine.

Adult↗
PubMed1998

[Comparative characterization of oxidative stress in some hereditary diseases differing in predisposition of neoplasms and early aging].

Two groups of hereditary diseases are considered. One group is characterized by chromosomal instability (Fanconi's anemia, ataxiatelenagioectasia, xeroderma pigmentosum). The other group includes diseases with marked genotypic changes (Down's disease, cystic fibrosis). All these diseases predispose to malignant neoplasms and premature ageing, which is due to different manifestations of oxidative stress. The paper gives in greatest detail the mechanism responsible for Fanconi's anemia which has been much studied by the authors. Chromosomal instability in this disease is associated with regeneration defect in DNA impaired by oxygen radicals.

Aging↗
PubMed1997

L-methionine induces stage-dependent changes of differentiation and oxidative activity in sea urchin embryogenesis.

This study was to investigate developmental toxicity of some selected low molecular weight antioxidants, by utilising sea urchin embryos and gametes as model system. Sea urchin embryos or sperm were exposed at different developmental stages to L-methionine or some selected low molecular weight antioxidants: a) N-acetylcysteine; b) L-carnosine; c) L-homocarnosine, and d) L-anserine. L-methionine displayed developmental toxicity at levels > or = 10(-5) M, whereas the other agents tested were mostly active at levels > or = 10(-4) M. When embryos were exposed to 10(-4) M L-methionine or N-acetylcysteine at different developmental stages, the most severe effects were exerted by early exposures (0 to 2 hr after fertilisation), whereas later exposures turned to lesser or no effects. Cytogenetic analysis of L-methionine-exposed embryos showed a significant mitogenic effect and increase of mitotic aberrations. Fertilisation success was decreased by L-methionine (10(-6) M to 10(-3) M) added at the moment of fertilisation, with increasing developmental and cytogenetic abnormalities in the offspring. The formation of reactive oxygen species in embryos and gametes was determined by: a) analysing the DNA oxidative product, 8-hydroxy-2'-deoxyguanosine (8-OHdG), and b) luminol-dependent chemiluminescence. The results showed that: 1) 8-OHdG levels were increased during embryogenesis; 2) fertilisation was associated with a double-wave luminol-dependent chemiluminescence emission; 3) luminol-dependent chemiluminescence was maximal in cleavage, declining down to zero in plutei, and 4) an embryotoxic L-methionine or N-acetylcysteine level (10(-4) M) turned to a decrease in reactive oxygen species formation. The data suggest that L-methionine- or N-acetylcysteine-induced developmental toxicity is confined to early stages. A role for oxidative activity is suggested in modulating cell differentiation and embryogenesis, consistent with antioxidant-induced damage to early life stages.

8-Hydroxy-2'-Deoxyguanosine↗