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1.
Int J Biometeorol ; 58(7): 1627-39, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24317795

ABSTRACT

Since the end of the last glacial period, European Mediterranean mountains have provided shelter for numerous species of Eurosiberian and Boreal origin. Many of these species, surviving at the southern limit of their range in Europe and surrounded by Mediterranean ones, are relatively intolerant to summer drought and are in grave danger of loss, as a result of increasingly long and frequent droughts in this region. This is the case of the Scots pine (Pinus sylvestris) and the Austrian pine (Pinus nigra ssp. salzmannii) which are found on Central Iberian Peninsula at the edge of their natural range. We used a tree ring network of these two species to reconstruct past variations in summer rainfall. The reconstruction, based upon a tree ring composite chronology of the species, dates back to 1570 (adjusted R(2) = 0.49, P < 0.000001) and captures interannual to decadal scale variability in summer precipitation. We studied the spatial representativeness of the rainfall patterns and described the occurrence rate of extremes of this precipitation. To identify associations between macroclimatic factors and tree radial growth, we employed a principal component analysis to calculate the resultant of the relationship between the growth data of both species, using this resultant as a dependent variable of a multiple regression whose independent variables are monthly mean temperature and precipitation from the average records. Spatial correlation patterns between instrumental precipitation datasets for southern Europe and reconstructed values for the 1950-1992 period indicate that the reconstruction captures the regional signal of drought variability in the study region (the origin of this precipitation is convective: thermal low pressure zones induced in the inland northeastern areas of the Iberian Peninsula). There is a clear increase in the recurrence of extreme dry events as from the beginning of twentieth century and an abrupt change to drier conditions. There appears to be a tendency toward recurrent exceptionally dry summers, which could involve a significant change for the Eurosiberian refugee species.


Subject(s)
Climate Change/history , Pinus/anatomy & histology , Pinus/growth & development , Altitude , History, 16th Century , History, 17th Century , History, 18th Century , History, 19th Century , History, 20th Century , Rain , Spain , Trees/anatomy & histology , Trees/growth & development
2.
Hematology ; 16(1): 37-42, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21269566

ABSTRACT

Bone marrow samples of 30 patients with de novo adult acute myeloid leukemia (AML) were analyzed for Wt1 and FLT3-internal tandem duplication (FLT3-ITD) expression measured by western blot and reverse transcription-polymerase chain reaction analysis, respectively. Wt1 was detected in 53·3% of AML patients (16/30), while FLT3-ITD in 23·3% (7/30). The high Wt1 expression correlated with the presence of FLT3-ITD (P = 0·014) and lower rate of complete remission (P = 0·023). The cumulative survival in AML patients was affected significantly by the presence of FLT3-ITD, being lower in the FLT3-ITD (+) group (6·0±2·4 months) compared to the FLT3-ITD (-) patients (17·9±3·3; P = 0·04). The expression of FLT3-ITD could probably activate Wt1 expression in AML blast cells and thus might contribute to its oncogenic function to provide cells with survival advantages in vivo. The detection of both molecular markers (Wt1 and/or FLT3-ITD) may be helpful in defining high risk AML patients that need special therapeutic strategies.


Subject(s)
Leukemia, Myeloid, Acute/metabolism , WT1 Proteins/biosynthesis , fms-Like Tyrosine Kinase 3/biosynthesis , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Female , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tandem Repeat Sequences , WT1 Proteins/genetics , WT1 Proteins/metabolism , fms-Like Tyrosine Kinase 3/genetics , fms-Like Tyrosine Kinase 3/metabolism
3.
J Neuroimmunol ; 225(1-2): 153-63, 2010 Aug 25.
Article in English | MEDLINE | ID: mdl-20466440

ABSTRACT

PI-2301 is an immunomodulator that could be an alternative therapy for MS. A placebo-controlled, multiple-ascending dose, double-blind study was performed in patients with secondary-progressive MS. Treatment was given subcutaneously once weekly for 8 weeks, followed by a 4-week open-label treatment period with active drug. The most common adverse event was transient injection site reactions. Non-significant trend for increases in serum levels of IL-3, IL-13, and CCL22 over time were suggestive of a beneficial T(H)2 immune response in subjects dosed with PI-2301 at 3 and 10 mg. MRI data indicated a non-significant trend for a reduction of lesion numbers in subjects treated with 1 and 3 mg PI-2301.


Subject(s)
Cytokines/metabolism , Multiple Sclerosis, Chronic Progressive/drug therapy , Multiple Sclerosis, Chronic Progressive/immunology , Peptides/therapeutic use , Th2 Cells/drug effects , Adult , Anti-Inflammatory Agents/blood , Anti-Inflammatory Agents/therapeutic use , Antibodies/blood , Dose-Response Relationship, Drug , Double-Blind Method , Female , Glatiramer Acetate , Humans , Magnetic Resonance Imaging/methods , Male , Middle Aged , Peptides/immunology , Severity of Illness Index , Treatment Outcome
4.
Akush Ginekol (Sofiia) ; 47(2): 16-20, 2008.
Article in Bulgarian | MEDLINE | ID: mdl-18642580

ABSTRACT

AIM OF THE STUDY: To analyse the influence of antithyroid antibodies (ATA) on the frequency of spontaneous abortions (SA) by pregnant women with a normal thyroid gland function. DESIGN OF THE STUDY: Prospective clinical study on 42 selected pregnant women with a normal thyroid gland function divided into two groups: I-st group--ATA positive pregnant [n = 28] and II-end group ATA negative pregnant [n = 14]. RESULTS: Increased ATA have been found by 30 (71.4%) out of the studied 42 pregnant women. There has been no significant difference found among the values of FT3, FT4 and TSH for women with positive and negative ATA. SA have been observed at 63.3% (19/30 women) from the ATA positive ones and at 25% (4/12 women) from the ATA negative ones (P = 0.001). By the ATA positive women with SA the average values of antithyroglobulin autoantibody (Tg-Ab) (Tg-Ab positive.-189.6 +/- 49.8 IU/ml vs. Tg-Ab -negative 118.2 +/- 58.3 IU/ml, P = 0.02) and antithyroid peroxidase autoantibody (TPO-Ab) (TPO-Ab positive-176.9 +/- 57.4 IU/ml vs. TPO - negative 118.2 +/- 81.3 IU/ml, P = 0.004) are both found to be significantly higher. CONCLUSION: There is a correlation found between ATA and the increased risk of SA, where the increased concentration of ATA is combined with an increased frequency of SA.


Subject(s)
Abortion, Spontaneous/epidemiology , Thyroiditis, Autoimmune/complications , Abortion, Spontaneous/etiology , Abortion, Spontaneous/immunology , Autoantibodies/blood , Female , Humans , Pregnancy , Prospective Studies , Thyroid Hormones/blood , Thyroiditis, Autoimmune/epidemiology , Thyroiditis, Autoimmune/immunology
5.
Biochim Biophys Acta ; 1777(7-8): 740-6, 2008.
Article in English | MEDLINE | ID: mdl-18454935

ABSTRACT

The supra-molecular assembly of the main respiratory chain enzymatic complexes in the form of "super-complexes" has been proved by structural and functional experimental evidence. This evidence strongly contrasts the previously accepted Random Diffusion Model stating that the complexes are functionally connected by lateral diffusion of small redox molecules (i.e. Coenzyme Q and cytochrome c). This review critically examines the available evidence and provides an analysis of the functional consequences of the intermolecular association of the respiratory complexes pointing out the role of Coenzyme Q and of cytochrome c as channeled or as freely diffusing intermediates in the electron transfer activity of their partner enzymes.


Subject(s)
Electron Transport , Mitochondria/metabolism , Oxidative Phosphorylation , Oxygen Consumption , Animals , Cytochromes c/chemistry , Cytochromes c/metabolism , Kinetics , Mitochondria/enzymology , Models, Molecular , Multienzyme Complexes/chemistry , Multienzyme Complexes/metabolism , NADH, NADPH Oxidoreductases/chemistry , NADH, NADPH Oxidoreductases/metabolism , Oxidoreductases/chemistry , Oxidoreductases/metabolism , Plant Proteins/chemistry , Plant Proteins/metabolism , Ubiquinone/chemistry , Ubiquinone/metabolism
6.
Akush Ginekol (Sofiia) ; 46(5): 17-22, 2007.
Article in Bulgarian | MEDLINE | ID: mdl-17974177

ABSTRACT

AIM OF STUDY: To follow the meaning of diabetic metabolic control in the early pregnancy springing up the preeclampsia (PR) in pregnant women with type I diabetes mellitus (T1DM). DESIGN OF STUDY: A prospective study has been done among 105 pregnant women with T1DM. The diabetic pregnant have been divided into two groups: 1st group--43 women with preplanning pregnancy and 2nd group--62 women with non-planning pregnancy. RESULTS: There was no difference in the frequency of PR among women with planning and non-planning pregnancy (25.6% vs. 30.6%; P=0.36). The mild and moderate cases of PR among the women with planning pregnancy are prevailing, while moderate and severe cases of PR were observed in non-planning pregnancy. In pregnant women with planning pregnancy there is no difference between the initial level HbA1c of women without PR and PR (7%+/-0.7 vs. 7.1%+/-0.9%; P=0.13). Pregnant women with non-planning pregnancy have significantly higher initial level of HbA1c (9.7%+/-1.7 vs. 8.3%+/-1.3%; P=0.01). Pregnant women with PR have significantly higher body weight, creatinin, diurnal urine albumin excretion and diurnal insulin dose. CONCLUSION: The chronicle hyperglycemia in the early pregnancy in combination with the established factors are increasing the risk of preeclampsia in women with non-planning pregnancy and poor glycaemic control.


Subject(s)
Diabetes Mellitus, Type 1/complications , Pre-Eclampsia/epidemiology , Pregnancy in Diabetics , Adult , Blood Glucose/analysis , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/epidemiology , Family Planning Services/statistics & numerical data , Female , Glycated Hemoglobin/analysis , Humans , Incidence , Pre-Eclampsia/blood , Pre-Eclampsia/etiology , Pre-Eclampsia/prevention & control , Pregnancy , Pregnancy in Diabetics/blood , Pregnancy in Diabetics/epidemiology , Prospective Studies , Risk Factors
7.
Akush Ginekol (Sofiia) ; 45(5): 3-9, 2006.
Article in Bulgarian | MEDLINE | ID: mdl-17168489

ABSTRACT

UNLABELLED: The incidence of spontaneous abortions in women with type 1 diabetes mellitus varies between 10-30%. The etiology of this is still unclear despite numerous experimental studies. Pregnancy is a condition of increased oxidative stress due to impaired balance between pro- and antioxidants. Glutathion and related enzymes perform the best antioxidant protection. Some authors point to a possible correlation between spontaneous abortions and low plasma Se levels as well as low intracellular activity of glutathion peroxidase enzyme. Others report that Hb A1-c, values over 1SD above normal increase the risk of spontaneous abortions with 3% and Hb A1-C values between 10-12% are critically high for the occurrence of spontaneous abortions. The purpose of the study was to evaluate the levels of Se and glutathion peroxidase enzyme (Gl-Px) in pregnant women with type 1 diabetes mellitus in the first trimester of pregnancy and to find out is there a correlation between glycemic control of diabetes and the incidence of spontaneous abortions. DESCRIPTION OF PROJECT: 75 pregnant women enrolled in an- 1 year prospective study divided in 3 groups according to pregnancy outcome: gr. 1 - n = 30 with type diabetes mellitus, no abortions, gr.2 - n = 16 with type diabetes mellitus with first trimester spontaneous abortion and gr. 3 - n = 29 healthy pregnant women. Women with type 1 diabetes mellitus were divided into three subgr. according to glycemic control - subgr. 1 - n = 12 (Hb A1-c < 7%), subgr.2 - n = 18 (Hb A1-c > 7< 8%), subgr.3 - n = 16 (Hb A1-c > 8%). Gl-Px activity was determined in Er hemolisate with test reagents of Randox Ransel, with ref.values 27.5 - 73 U/g Hb. Selen concentration was determined in whole blood sample by atomic absorption spectrophotometry with ref. values 0.12-1.1 micromol/l. HbA 1-C was measured by affinity chromatography with ref. values 4.5-6.3%. Statistical methods used were: dispersion, correlation analysis - SPSS package version 11.01.01. RESULTS: Basic Se levels were low in all pregnant women in early pregnancy. The metabolic control level did not influence the levels of Se in pregnant women with diabetes mellitus type1. Gl -Px activity was within the normal limits in all women. There was no correlation between Se levels and Gl -Px activity in pregnant diabetics with and without abortions. There was a correlation between Se levels and Gl -Px activity only in healthy pregnant women. Pregnant women with poor glycemic control had higher incidence of spontaneous abortions. CONCLUSIONS: We could not support the hypothesis of reduced antioxidant protection (low Se and Gl-Px levels) as a causative factor in the pathogenesis of spontaneous abortions in diabetic patients. Our study results showed that poor metabolic control of diabetes (high Hb A1-c) in the first trimester of pregnancy had a primary role in the occurrence of early abortions. We could speculate that the early hyperglycemic maternal-fetal environment most probably plays a role of an additional stress to the developing embryo.


Subject(s)
Abortion, Spontaneous , Diabetes Mellitus, Type 1 , Glutathione Peroxidase/metabolism , Pregnancy in Diabetics , Selenium/blood , Abortion, Spontaneous/enzymology , Abortion, Spontaneous/etiology , Abortion, Spontaneous/metabolism , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/enzymology , Diabetes Mellitus, Type 1/metabolism , Erythrocytes/enzymology , Female , Glycated Hemoglobin/analysis , Humans , Pregnancy , Pregnancy Trimester, First , Pregnancy in Diabetics/enzymology , Pregnancy in Diabetics/metabolism , Prospective Studies
8.
Akush Ginekol (Sofiia) ; 44(4): 3-10, 2005.
Article in Bulgarian | MEDLINE | ID: mdl-16028370

ABSTRACT

UNLABELLED: The pregnancies in women with Diabetes mellitus are in condition of increased glucooxidative stress, which could be toxic for the developing embryo. END-POINTS: To evaluate the levels of selenium and glutation peroxidase in pregnant women with Diabetes mellitus type 1 in the first trimester of pregnancy and to establish whether there is a correlation between the diabetic glycemic control and occurrence of spontaneous abortions. STUDY DESIGN: Prospective study of 75 women for 1 year period. he pregnant women were divided in 3 groups as follows: 1st group--30 pregnant women with Diabetes mellitus type 1 with normal outcome; 2nd group--16 pregnant women with Diabetes mellitus type 1 with spontaneous abortion; 3rd group--29 healthy pregnant controls. The activity of GI-Px in red blood cells was measured in hemolysat of EDTA plasma in Germany. The levels of glucosylated haemoglobin were also evaluated. RESULTS: 1. In all pregnant women the levels of selenium were lower without significant difference between them 1st group--0.12 +/- 0.6 mmol/l, 2ndd group 0.13 +/- 0.1 mmol/l, 3rd group 0.13 +/- 0.7 mmol/l (P > 0.05). 2. There is an increase in the activity of GI-Px, which is statistically significant in the healthy pregnant women 47.8 +/- 13.3 U/g Hb and diabetic pregnant women with normal outcome 48. 6 +/- 8.4 U/g Hb. There is no statistically significant difference in the activity of GI-Px in diabetic pregnant women with spontaneous abortions and the healthy controls (P > 0. 05). 3. Negative correlation between the levels of selenium and the activity of GI-Px was proved in healthy pregnant women (r = - 0.4; P < 0.05). No correlation was found between the level of the selenium and the activity of GI-Px into the two groups of diabetic pregnant women. 4. There is a correlation in the levels of diabetic pregnant women with spontaneous abortions (r = -0.38; P < 0.001). CONCLUSIONS: The increased activity of GI-Px in diabetic pregnant women with spontaneous abortions is a result of increased antioxidative defense of the cell. Probably the ineffective antioxidant defense, leading to a spontaneous abortion is due to the low levels of selenium and high level of pre-prandial glycaemia.


Subject(s)
Abortion, Spontaneous/etiology , Diabetes Mellitus, Type 1 , Glutathione Peroxidase/blood , Oxidative Stress , Pregnancy in Diabetics , Selenium/blood , Abortion, Spontaneous/blood , Abortion, Spontaneous/metabolism , Adult , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/metabolism , Female , Gestational Age , Humans , Pregnancy , Pregnancy in Diabetics/blood , Pregnancy in Diabetics/complications , Pregnancy in Diabetics/metabolism , Prospective Studies
9.
Akush Ginekol (Sofiia) ; 44(3): 3-10, 2005.
Article in Bulgarian | MEDLINE | ID: mdl-16028383

ABSTRACT

PURPOSE: To evaluate the correlation between maternal hyperglycemia in early pregnancy and the risk of fetal abnormalities in pregnant women with type 1 diabetes mellitus. STUDY DESIGN: A retrospective study over 124 pregnant women with diabetes mellitus type 1 hospitalized in High Risk Pregnancy Department--SHATOG "Maichin dom" has been done from January. 1998 to January 2004. The diabetic pregnant women were divided in two groups: first group pregnant women without malformations n = 105 and second group pregnant women with malformations n = 19. The pregnant women with fetal malformations were divided into two subgroups: with major malformations n = 13 and with minor malformations n = 6. The diabetic pregnant women were divided in classes according to Whites Classification: Class B - 38, Class C - 35; Class D - 39 and Class R/F - 12. The values of preprandial glucose, postprandial glucose and glycosilated hemoglobin has been measured at 13 week of gestation. RESULTS: 104 pregnancies of total 124 pregnancies were without abnormalities. The fetal malformations were observed in 19 (15.3%) of total 124 pregnancies. The rate of major abnormalities were - 13 (10.4%) and minor abnormalities were - 7 (5.6%). The highest rate of abnormalities there has been within the complicated diabetic women of class D - n = 7 (17.9 %) and class R/F n = 3 (25%). The initial values of preprandial glucose 9.54 (SD +/- 3.59) mmol/l and postprandiai glucose 10.52 (SD +/- 1.81) mmol/l between the women whit pregnancies with abnormalities were significantly higher then those values of preprandial glucose 7.39 (SD +/- 2.82) mmol/l (P - 0.021) and values of postprandial glucose 10.52 (SD +/- 1.81) mmol/l (P = 0.014) between the women without fetal malformations. The mean values of glycosilated hemoglobin were significantly higher HbA 1 c = 9. 01% (SD +/- 1.53) in pregnancies complicated with malformations than those values measured in pregnancies without fetal malformations 8.06% (SD +/- 1.64, P = 0.022). A positive correlation between the observed abnormalities and metabolic control in the early pregnancy exist. The values of Hbeta A1-c is significantly higher Hbeta A1-c - 9.9% (SD +/- 1.2) in pregnancies complicated with fetal malformations than those measured in pregnancies without malformations. Hbeta A1-c 8.2% (SD +/- 1.5) n = 125. Significant differences in the value of Hbeta A1-c between pregnancies with mild and those with severe abnormalities have not been established. A correlation between the levels of Hbeta A1-c in early pregnancy and the rate of the observed abnormalities exist. Within the values of Hbeta A1-c < 7.9%, the rate of malformations is 6.9%, Hbeta A1-c > 8.0% < 10%, the rate of malformations is 19.0% and within the values of Hbeta A1-c > 10%, the rate of the observed abnormalities is 31.5%. A logistic regression between the higher values of postprandial glucose and Hbeta A1-c values and the relative risk of congenital malformations has been observed. The relative risk is evaluated by odds ratio (OR) When the levels of Hbeta A1-c rise with 1% the relative risk of congenital malformations is evaluated by odds ratio OR = 2.02 (limited in 1.46 - 2.81 by 95% conf. interval) and when the levels of postprandial glucose rise with 1 mmol/l the relative risk OR = 1.21 (limited in 1.06 - 1.37: 95% conf. interval). CONCLUSION: Fetal abnormalities are more frequent in pregnant women with long lasting diabetes complicated with vasculopathy. Fetal abnormalities are associated with higher levels of Hbeta A1-c in the first trimester of pregnancy. In diabetic women who planed their pregnancy an optimal metabolic control must been established.


Subject(s)
Congenital Abnormalities/epidemiology , Diabetes Mellitus, Type 1/blood , Glycated Hemoglobin/analysis , Pregnancy in Diabetics/blood , Ultrasonography, Prenatal , Blood Glucose/analysis , Congenital Abnormalities/diagnostic imaging , Congenital Abnormalities/embryology , Congenital Abnormalities/etiology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/epidemiology , Drug Administration Schedule , Female , Humans , Insulin/administration & dosage , Insulin/therapeutic use , Logistic Models , Pregnancy , Pregnancy in Diabetics/complications , Pregnancy in Diabetics/drug therapy , Pregnancy in Diabetics/epidemiology , Retrospective Studies , Severity of Illness Index
10.
Akush Ginekol (Sofiia) ; 43(7): 16-23, 2004.
Article in Bulgarian | MEDLINE | ID: mdl-15673049

ABSTRACT

UNLABELLED: Pregnant women with diabetes mellitus type 1 and poor metabolic control are with high frequency of spontaneous abortion. PURPOSE: To determine the correlation between the poor glycaemic control of diabetes in early pregnancy and the risk of spontaneous abortion. DESIGN OF STUDY: A prospective study over 116 women with type 1 diabetes mellitus who have been hospitalized in SHATOG "Maichin dom" during the period: January 1998-January 2004 have been done. The pregnant women have been divided in two groups. Pregnant women with pre-planned pregnancy n = 44 and pregnant women with unplanned pregnancy n = 72. The levels of pre- and postprandial blood glucose and those of glycosylated hemoglobin Hb A1c at first trimester have been measured. RESULTS: In 20 of all pregnant women (17.2%) spontaneous abortion have been observed. In those women with abortion the initial glycaemia has been significantly higher-preprandial glucose is 10.2 +/- 3.4 mmol/l and postprandial glucose is 12.2 +/- 4.2 mmol/l in contrast to those in women without abortions--preprandial glucose 6.6 +/- 1 mmol/l postprandial glucose is 7.9 +/- 1.9 mmol/l. The mean values of Hb A1c at first trimester have been higher in those women with abortions--10.1% +/- 1.5 in contrast to those without abortions 7.0% +/- 0.7. CONCLUSION: The pregnant women with diabetes type 1 and higher initial levels of blood glucose and glycosylated hemoglobin in the first trimester of pregnancy have a higher risk of spontaneous abortions. The rate of spontaneous abortions in diabetic women with pre-planned pregnancy and optimized metabolic control before conception is lower.


Subject(s)
Abortion, Spontaneous/epidemiology , Blood Glucose/metabolism , Diabetes Mellitus, Type 1/complications , Hyperglycemia/complications , Pregnancy in Diabetics/blood , Bulgaria/epidemiology , Female , Glycated Hemoglobin/analysis , Humans , Incidence , Pregnancy , Pregnancy Trimester, First , Retrospective Studies , Risk Factors
11.
Cell Mol Life Sci ; 60(8): 1752-9, 2003 Aug.
Article in English | MEDLINE | ID: mdl-14504660

ABSTRACT

The pattern of cytochrome c oxidase inhibition by nitric oxide (NO) was investigated polarographically using Keilin-Hartree particles, mitochondria and human neuroblastoma cells. NO reacts with purified cytochrome c oxidase forming either a nitrosyl- or a nitrite-inhibited derivative, displaying distinct kinetics and light sensitivity of respiration recovery in the absence of free NO. Keilin-Hartree particles or cells, respiring either on endogenous substrates alone or in the presence of ascorbate, as well as state 3 and state 4 mitochondria respiring on glutamate and malate, displayed the rapid recovery characteristic of the nitrite derivative. All systems, when respiring in the presence of tetramethyl-p-phenylenediamine, were characterised by the slower, light-sensitive recovery typical of the nitrosyl derivative. Together the results suggest that the reaction of NO with cytochrome c oxidase in situ follows two alternative inhibition pathways, depending on the electron flux through the respiratory chain.


Subject(s)
Cell Respiration/physiology , Mitochondria, Liver/metabolism , Neuroblastoma/metabolism , Nitric Oxide/metabolism , Animals , Cattle , Electron Transport Complex IV/antagonists & inhibitors , Humans , In Vitro Techniques , Male , Mice , Mice, Inbred BALB C , Models, Biological , Myocardium/metabolism , Polarography , Rats , Rats, Wistar , Tumor Cells, Cultured
12.
J Cancer Res Clin Oncol ; 128(5): 271-8, 2002 May.
Article in English | MEDLINE | ID: mdl-12029443

ABSTRACT

PURPOSE: The purpose of this study was to characterise bendamustine's cytotoxic and apoptotic activity in a panel of leukemia and breast cancer cell lines in comparison to its clastogenicity in murine bone marrow. METHODS: The cytotoxic effect of bendamustine was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT)-dye reduction assay. Induction of apoptosis was evidenced by DNA gel electrophoresis, nuclear staining, Western blot poly-(adenosine diphosphate-ribose) polymerase (PARP) cleavage, and flow cytometry. As a measure of hematological toxicity, the formation of chromosomal aberrations was investigated in bone marrow cells isolated from mice treated with low non-toxic doses of bendamustine and lomustine. RESULTS: Bendamustine was preferably active against leukemic cells of lymphoid origin and was found to induce apoptosis in SKW-3 and BV-173 cells as shown by oligonucleosomal DNA and nuclear fragmentation, PARP cleavage, and formation of a sub-G1 fraction. Myeloid and breast carcinoma cell lines were resistant towards bendamustine with the exception of HL-60 cells which exhibit an intermediate sensitivity. Bendamustine was found to have a very low clastogenic effect as compared with equimolar doses of lomustine. CONCLUSION: Taken together, the mode of action of bendamustine includes induction of apoptosis. The specific spectrum of activity and the unexpectedly low clastogenicity support the hypothesis that bendamustine in not a typical alkylating agent but exerts an additional mode of action, possibly as a purine antimetabolite.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Bone Marrow Cells/drug effects , Breast Neoplasms/drug therapy , Leukemia/drug therapy , Nitrogen Mustard Compounds/pharmacology , Animals , Antineoplastic Agents/therapeutic use , Bendamustine Hydrochloride , Bone Marrow Cells/pathology , Breast Neoplasms/pathology , Flow Cytometry , HL-60 Cells , Humans , Leukemia/pathology , Mice , Nitrogen Mustard Compounds/therapeutic use , Tumor Cells, Cultured
13.
FEBS Lett ; 505(3): 364-8, 2001 Sep 21.
Article in English | MEDLINE | ID: mdl-11576529

ABSTRACT

The mitochondrial respiratory chain is a powerful source of reactive oxygen species, considered as the pathogenic agent of many diseases and of aging. We have investigated the role of Complex I in superoxide radical production in bovine heart submitochondrial particles and found, by combined use of specific inhibitors of Complex I and by Coenzyme Q (CoQ) extraction from the particles, that the one-electron donor in the Complex to oxygen is a redox center located prior to the binding sites of three different types of CoQ antagonists, to be identified with a Fe-S cluster, most probably N2 on the basis of several known properties of this cluster. Short chain CoQ analogs enhance superoxide formation, presumably by mediating electron transfer from N2 to oxygen. The clinically used CoQ analog, idebenone, is particularly effective in promoting superoxide formation.


Subject(s)
Iron-Sulfur Proteins/metabolism , Mitochondria, Heart/enzymology , NADH, NADPH Oxidoreductases/metabolism , Superoxides/metabolism , Ubiquinone/metabolism , Animals , Cattle , Coenzymes , Electron Transport Complex I , Enzyme Inhibitors/pharmacology , Hydroxymercuribenzoates/pharmacology , Mitochondria, Heart/drug effects , NADH, NADPH Oxidoreductases/antagonists & inhibitors , Oxidation-Reduction , Submitochondrial Particles/drug effects , Submitochondrial Particles/enzymology , Ubiquinone/analogs & derivatives
14.
Clin Chim Acta ; 310(1): 53-6, 2001 Aug 01.
Article in English | MEDLINE | ID: mdl-11485755

ABSTRACT

Assessment of renal function in clinical medicine is of great importance especially in patients with renal transplants. Cystatin C has the characteristics of an ideal marker to assess renal glomerular filtration rate. Forty patients with renal transplants under steady-state post-transplant conditions were included in the study. Steady-state was defined as lack of acute rejection periods during the last 6 months and stable cyclosporin A medication during the past 4 weeks. Gender was balanced with 20 male and 20 female patients, the mean age was 51+/-14 years, time since transplantation was 5+/-3.5 years. Fifteen percent of the patients suffered from diabetes mellitus. Immunosuppression consisted of cyclosporin A, imuran, and prednisolon. To assess renal function cystatin C, creatinine clearance, serum creatinine, and serum beta2-microglobulin were tested. Creatinine was analysed in serum and urine to calculate the creatinine clearance related to 1.73 m(2) body surface. Cystatin C and beta2-microglobulin were determined by using a particle-enhanced turbidimetric assay. Cystatin C correlated best with creatinine clearance (r=0.66), beta2-microglobulin (0.57), and serum creatinine (0.56). The diagnostic accuracy of cystatin C was significantly better than serum creatinine (p<0.05), but did not differ significantly from creatinine clearance (p=0.73), and beta2-microglobulin (p=0.46). Our data show that patients with renal transplants, cystatin C has a similar diagnostic value as creatinine clearance. However, it is superior to serum determination of creatinine and beta2-microglobulin. Cystatin C allows for rapid and accurate assessment of renal function in patients with renal transplants and is clearly superior to the commonly used serum creatinine.


Subject(s)
Cystatins/blood , Kidney Transplantation , Adult , Aged , Cystatin C , Female , Humans , Male , Middle Aged , Sensitivity and Specificity
15.
Ophthalmologica ; 215(1): 51-4, 2001.
Article in English | MEDLINE | ID: mdl-11125270

ABSTRACT

To seek some specific biochemical markers of age-related macular degeneration (AMD), coenzyme Q10 (CoQ10) levels were determined in plasma and platelets from 19 exudative AMD patients and 19 age-matched controls. Lipid peroxidation was followed in plasma in vitro after the addition of a free radical initiator. Most patients had lower plasma CoQ10 content than most controls. Plasma from controls showed greater capacity to oppose the oxidative damage. These results support the concept that free radicals play a pathogenic role in AMD and that CoQ10 may have a protective effect.


Subject(s)
Antioxidants/analysis , Macular Degeneration/blood , Oxidative Stress , Ubiquinone/blood , Aged , Biomarkers/blood , Coenzymes , Female , Free Radicals , Humans , Lipid Peroxidation , Male , Pilot Projects , Thiobarbituric Acid Reactive Substances/metabolism , Ubiquinone/analogs & derivatives
16.
Biochim Biophys Acta ; 1459(2-3): 397-404, 2000 Aug 15.
Article in English | MEDLINE | ID: mdl-11004456

ABSTRACT

Mitochondria are strongly involved in the production of reactive oxygen species, considered as the pathogenic agent of many diseases and of aging. The mitochondrial theory of aging considers somatic mutations of mitochondrial DNA induced by oxygen radicals as the primary cause of energy decline; experimentally, complex I appears to be mostly affected and to become strongly rate limiting for electron transfer. Mitochondrial bioenergetics is also deranged in human platelets upon aging, as shown by the decreased Pasteur effect (enhancement of lactate production by respiratory chain inhibition). Cells counteract oxidative stress by antioxidants; among lipophilic antioxidants, coenzyme Q is the only one of endogenous biosynthesis. Exogenous coenzyme Q, however, protects cells from oxidative stress by conversion into its reduced antioxidant form by cellular reductases.


Subject(s)
Aging/physiology , Energy Metabolism , Mitochondria/physiology , Animals , Antioxidants/analysis , Antioxidants/metabolism , Antioxidants/pharmacology , Blood Platelets/physiology , Coenzymes , Electron Transport Complex I , Humans , Macular Degeneration/metabolism , Mitochondria/genetics , Mitochondria/metabolism , Mitochondria, Heart/metabolism , Mitochondria, Muscle/metabolism , NADH, NADPH Oxidoreductases/metabolism , Oxidative Stress/drug effects , Rats , Reactive Oxygen Species/metabolism , Ubiquinone/analogs & derivatives , Ubiquinone/analysis , Ubiquinone/metabolism , Ubiquinone/pharmacology
17.
Biofactors ; 9(2-4): 87-93, 1999.
Article in English | MEDLINE | ID: mdl-10416019

ABSTRACT

We have studied the mobility of coenzyme Q (CoQ) in lipid bilayers and mitochondrial membranes in relation to the control of electron transfer activities. A molecular dynamics computer simulation in the vacuum yielded a folded structure for CoQ10, with a length of only 21 A. Using this information we were able to calculate diffusion coefficients in the range of 10(-6) cm2/s in good agreement with those found experimentally by fluorescence quenching of pyrene derivatives. To investigate if CoQ diffusion may represent the rate-limiting step of electron transfer, we reconstituted complexes I and III and assayed the resulting NADH-cytochrome c reductase activity in presence of different CoQ10 levels and at different distances between complexes; the experimental turnovers were higher than the collision frequencies calculated using diffusion coefficients of 10(-9) cm2/s but compatible with values found by us by fluorescence quenching. Since the experimental turnovers are independent of the distance between complexes, we conclude that CoQ diffusion is not rate-limiting for electron transfer.


Subject(s)
Intracellular Membranes/metabolism , Lipid Bilayers/chemistry , Mitochondria/metabolism , Ubiquinone/chemistry , Ubiquinone/metabolism , Animals , Computer Simulation , Electron Transport , Intracellular Membranes/chemistry , Mitochondria/chemistry , Models, Molecular , Molecular Conformation , Ubiquinone/analogs & derivatives
18.
Biofactors ; 9(2-4): 345-9, 1999.
Article in English | MEDLINE | ID: mdl-10416051

ABSTRACT

In a surgical model of liver ischemia lipid peroxidation occurs, as shown by increase of lipid peroxidation end products, endogenous CoQ9 is oxidized and mitochondrial respiration is lowered; however, pre-treatment of the rats by i.p. injection of CoQ10 for 14 days normalizes the above parameters, presumably by way of the observed high extent of reduction of the incorporated quinone; moreover, liver homogenates of the CoQ10-treated rats are more resistant than those of non-treated rats to oxidative stress induced by an azido free radical initiator. This preliminary study suggests that CoQ10 pre-treatment can be of beneficial effect against oxidative damage during liver surgery transplantation.


Subject(s)
Ischemia/physiopathology , Liver/blood supply , Reperfusion Injury/prevention & control , Ubiquinone/pharmacology , Amidines/pharmacology , Animals , Antioxidants/metabolism , Lipid Peroxidation/drug effects , Liver/drug effects , Liver/metabolism , Oxidants/pharmacology , Rats , Reperfusion , Ubiquinone/analogs & derivatives , Ubiquinone/metabolism , Vitamin A/metabolism , Vitamin E/metabolism
20.
Cell Mol Biol (Noisy-le-grand) ; 44(4): 597-604, 1998 Jun.
Article in English | MEDLINE | ID: mdl-9678895

ABSTRACT

One characteristic feature of the aged central nervous system (CNS) is neuron loss. Programmed cell death (PCD) has been implicated in neuronal death during development and may be involved in a number of age-related neurodegenerative diseases of the CNS. Cell death in the aging cerebral cortex was investigated in the present morphometric and immunohistochemical study of rat frontal cortex by detection of bcl-2 as the factor preventing PCD. The results were interpreted in the light of the bioenergetic features of aged motoneuron cells. Our results showed that 1) bcl-2 does not influence neuronal survival, and ii) the presence in aging frontal cortex of minor cellular morphometric and bioenergetic modifications, confirming the difference between normal aging and neurodegenerative disease.


Subject(s)
Aging , Cerebral Cortex/anatomy & histology , Aging/metabolism , Animals , Cell Death , Cellular Senescence , Cerebral Cortex/blood supply , Cerebral Cortex/metabolism , Fluorescent Antibody Technique , Immunohistochemistry , Male , Microscopy, Electron , Mitochondria/ultrastructure , Proto-Oncogene Proteins c-bcl-2/metabolism , Rats , Rats, Wistar
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