Publications by authors named "Marzena Wojcik"

30 Publications

  • Page 1 of 1

Identification of a novel association for the WWOX/HIF1A axis with gestational diabetes mellitus (GDM).

PeerJ 2021 14;9:e10604. Epub 2021 Jan 14.

Department of Molecular Carcinogenesis, Medical University of Lodz, Lodz, Poland.

Background: Although the WW-domain-containing oxidoreductase (WWOX)/Hypoxia-inducible factor 1 (HIF1) pathway is a well-known regulator of cellular glucose and energy metabolism in pathophysiological processes, its role in gestational diabetes mellitus (GDM), remains elusive. We undertook this study to determine the effect of WWOX/HIF1A signaling on the expression of glucose metabolism genes in GDM patients.

Methods: Leukocytes were obtained from 135 pregnant women with ( = 98) or without ( = 37) GDM and, in turn, 3 months ( = 8) and 1 year ( = 12) postpartum. Quantitative RT-PCR was performed to determine gene expression profiles of the WWOX/HIF1A-related genes, including those involved in glucose transport (), glycolytic pathway (), Wnt pathway (), and inflammatory response ().

Results: GDM patients displayed a significant downregulation of with simultaneous upregulation of which resulted in approximately six times reduction in ratio. As a consequence, induced genes () were found to be overexpressed in GDM compared to normal pregnancy and negative correlate with ratio. The postpartum expression was higher than during GDM, but its level was comparable to that observed in normal pregnancy.

Conclusions: The obtained results suggest a significant contribution of the gene to glucose metabolism in patients with gestational diabetes. Decreased expression in GDM compared to normal pregnancy, and in particular reduction of ratio, indicate that WWOX modulates HIF1α activity in normal tissues as described in the tumor. The effect of HIF1α excessive activation is to increase the expression of genes encoding proteins directly involved in the glycolysis which may lead to pathological changes in glucose metabolism observed in gestational diabetes.
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http://dx.doi.org/10.7717/peerj.10604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811782PMC
January 2021

Continuous subcutaneous insulin infusion does not correspond with pregnancy outcomes despite better glycemic control as compared to multiple daily injections in type 1 diabetes - Significance of pregnancy planning and prepregnancy HbA1c.

Diabetes Res Clin Pract 2021 Feb 22;172:108628. Epub 2020 Dec 22.

Department of Internal Diseases and Diabetology, Medical University of Lodz, Poland.

Objective: The aim of the study was to compare pregnancy outcomes with glycemic control, total increase in insulin requirement, and body weight gain in the women with Type 1 Diabetes Mellitus (T1DM) using continuous subcutaneous insulin infusion (CSII) or multiple daily injections (MDI).

Material And Methods: This was a single center retrospective observational study involving 209 pregnant Caucasian women. Among the study participants, 95 subjects were treated with MDI and 114 patients were using CSII therapy. The primary outcomes were pregnancy results, while secondary ones were HbA1c, increase in daily dose of insulin (DDI), and body weight gain.

Results: At baseline, the CSII users were older (P = 0.0373), they were diagnosed with T1DM at a younger age (P = 0.047), and more often planned pregnancy (P = 0.032). A majority of the women were classified as class D, according to the White classification. Among the CSII users, a significantly higher proportion of the subjects in class B was noted than in the MDI users, with no differences in the proportion of the remaining White classes. Prepregnancy HbA1c was insignificantly lower in the CSII group, however, a significantly higher proportion of the CSII users reached the target value of HbA1c (P = 0.008). A prepregnancy daily dose of insulin (both total and per kg of body weight), body weight, and body mass index (BMI) did not differ between the groups. The 1st and 2nd trimester HbA1c was lower among the CSII users (6.83 ± 1.38 vs 7.52 ± 2.11%, P = 0.01 and 6.17 ± 0.9 vs 6.57 ± 1.12%, P = 0.009, respectively), while the 3rd trimester HbA1c as well as the total change in HbA1c were comparable. Neither DDI and body weight in concecutive trimesters, nor their total gestational increase, differed between the groups. The rate of pregnancy loss, such as abortions, fetal and neonatal death did not differ between the groups. As regards composite pregnancy loss, prepregnancy HbA1c was 8.41%±2.81% among the MDI cohort vs 7.22%±1.31% in the CSII users (P = 0.517). No differences were found in the gestational age at delivery, the mode of delivery, neonatal birth weight, the rate of macrosomy, LGA or SGA. A higher Apgar score was noted among the CSII users (8.63 ± 1.63 vs 8.03 ± 2.49%, P = 0.047), however, the proportion of neonates with an Apgar score lower than 7 points was similar. In the women planning pregnancy, as compared to the subjects who did not, HbA1c was significantly lower in the 1st trimester, together with a significantly higher rate of the women achieving the target HbA1c value during planning as well as in the 1st trimester. In the group of women planning pregnancy, significantly lower 1st trimester HbA1c and composite outcome of pregnancy loss were observed in the CSII users vs the MDI treated women. Lack of pregnancy planning and a high HbA1c level in the 1st trimester were independent predictors of both LGA (OR = 4.99 [95%CI 1.12-21.0], P = 0.033 and OR = 3.02 [95%CI 1.19-7.65], P = 0.019, respectively) and macrosomia (OR = 8.43 [95%CI 1.36-51.93], P = 0.021 and OR = 5.47 [95%CI 1.77-16.87], P = 0.003, respectively).

Conclusions: The course of pregnancy and obstetric outcomes were not dependent on the mode of insulin delivery, but only on pregnancy planning and HbA1c in early pregnancy. Further studies are needed to explore more precise parameters describing both glycemic control in pregnant women as well as perinatal infant well-being.
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http://dx.doi.org/10.1016/j.diabres.2020.108628DOI Listing
February 2021

Impact of Foehn Wind and Related Environmental Variables on the Incidence of Cardiac Events.

Int J Environ Res Public Health 2020 04 12;17(8). Epub 2020 Apr 12.

Institute of Health Sciences, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland.

In Poland there is no data related to the impact of halny wind and the related environmental variables on the incidence of cardiac events. We decided to investigate the relationship between this weather phenomenon, as well as the related environmental variables, and the incidence of cardiac events in the population of southern Poland, a region affected by this type of wind. We also decided to determine whether the environmental changes coincide with or predate the event examined. We analysed data related to 465 patients admitted to the cardiology ward in a large regional hospital during twelve months of 2011 due to acute myocardial infarction. All the patients in the study group lived in areas affected by halny wind and at the time of the event were staying in those areas. The frequency of admissions on halny days did not differ significantly from the admissions on the remaining days of the year ( = 0.496). No statistically significant differences were found between the number of admissions on halny days and on the remaining days during halny months ( = 0.084). We have identified a difference in the number of admissions between days with no halny and days immediately preceding onset of halny ( = 0.001). However, no effects of the related environmental variables have been observed in the incidence of cardiac events ( = 0.866, F = 0.37). On the days with halny wind, incidence of cardiac events is similar to that on the remaining days of the year.
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http://dx.doi.org/10.3390/ijerph17082638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215363PMC
April 2020

The Influence of Dietary Fatty Acids on Immune Responses.

Nutrients 2019 Dec 6;11(12). Epub 2019 Dec 6.

Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 7265 Davos Wolfgang, Switzerland.

Diet-derived fatty acids (FAs) are essential sources of energy and fundamental structural components of cells. They also play important roles in the modulation of immune responses in health and disease. Saturated and unsaturated FAs influence the effector and regulatory functions of innate and adaptive immune cells by changing membrane composition and fluidity and by acting through specific receptors. Impaired balance of saturated/unsaturated FAs, as well as -6/-3 polyunsaturated FAs has significant consequences on immune system homeostasis, contributing to the development of many allergic, autoimmune, and metabolic diseases. In this paper, we discuss up-to-date knowledge and the clinical relevance of the influence of dietary FAs on the biology, homeostasis, and functions of epithelial cells, macrophages, dendritic cells, neutrophils, innate lymphoid cells, T cells and B cells. Additionally, we review the effects of dietary FAs on the pathogenesis of many diseases, including asthma, allergic rhinitis, food allergy, atopic dermatitis, rheumatoid arthritis, multiple sclerosis as well as type 1 and 2 diabetes.
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http://dx.doi.org/10.3390/nu11122990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950146PMC
December 2019

Expression Profile of Diabetes-Related Genes Associated with Leukocyte Sirtuin 1 Overexpression in Gestational Diabetes.

Int J Mol Sci 2018 Nov 30;19(12). Epub 2018 Nov 30.

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, 90-752 Lodz, Poland.

Although compelling evidence indicates that Sirtuin 1 (SIRT1) plays a prominent role in type 2 diabetes, its relationship with gestational diabetes (GDM) remains elusive. This study was aimed at identifying diabetes-related genes and cellular pathways linked to changes of leukocyte expression at the time of GDM diagnosis. For this purpose, 122 GDM patients were screened for leukocyte expression, and two subgroups were distinguished, namely GDM/(↑) ( = 30, < 0.05) and GDM/(↔) ( = 92, > 0.05), with significant and insignificant changes in leukocyte expression compared to a normal glucose tolerant (NGT) group ( = 41), respectively. PCR array analysis identified 11 diabetes-related genes with at least a ± 2-fold difference in expression in GDM/(↑) patients ( = 9) vs. NGT controls ( = 7); in addition, significant differences in the expression of four of the six investigated genes were confirmed between the entire GDM/(↑) group and the whole NGT group ( < 0.05). Interestingly, of these four genes, only expression was found to significantly differ between GDM/(↑) and GDM/(↔). This study demonstrates that under hyperglycemic conditions, leukocyte overexpression is accompanied by an over-abundance of three transcripts and an under-abundance of another; these four govern related metabolism, inflammation, and transport functions, suggesting that such alterations might represent systemic biological adaptations with a unique under-expression in GDM/(↑) women.
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http://dx.doi.org/10.3390/ijms19123826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321739PMC
November 2018

Molecular Mechanisms Underlying Curcumin-Mediated Therapeutic Effects in Type 2 Diabetes and Cancer.

Oxid Med Cell Longev 2018 20;2018:9698258. Epub 2018 Mar 20.

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, ul. Zeligowskiego 7/9, 90-752 Lodz, Poland.

The growing prevalence of age-related diseases, especially type 2 diabetes mellitus (T2DM) and cancer, has become global health and economic problems. Due to multifactorial nature of both diseases, their pathophysiology is not completely understood so far. Compelling evidence indicates that increased oxidative stress, resulting from an imbalance between production of reactive oxygen species (ROS) and their clearance by antioxidant defense mechanisms, as well as the proinflammatory state contributes to the development and progression of the diseases. Curcumin (CUR; diferuloylmethane), a well-known polyphenol derived from the rhizomes of turmeric , has attracted a great deal of attention as a natural compound with beneficial antidiabetic and anticancer properties, partly due to its antioxidative and anti-inflammatory actions. Although this polyphenolic compound is increasingly being recognized for its growing number of protective health effects, the precise molecular mechanisms through which it reduces diabetes- and cancer-related pathological events have not been fully unraveled. Hence, CUR is the subject of intensive research in the fields Diabetology and Oncology as a potential candidate in the treatment of both T2DM and cancer, particularly since current therapeutic options for their treatment are not satisfactory in clinics. In this review, we summarize the recent progress made on the molecular targets and pathways involved in antidiabetic and anticancer activities of CUR that are responsible for its beneficial health effects.
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http://dx.doi.org/10.1155/2018/9698258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884026PMC
October 2018

Melatonin as a Pleiotropic Molecule with Therapeutic Potential for Type 2 Diabetes and Cancer.

Curr Med Chem 2017 Nov;24(35):3829-3850

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, Lodz, Poland.

Background: The incidence of both type 2 diabetes (T2DM) and cancer is increasing worldwide, making these diseases a global health problem along with increasing healthcare expenditures. The current therapeutic approaches for treating these multifactorial diseases are far from satisfactory. As increasing evidence shows beneficial effects of melatonin (MLT) on typical pathological changes occurring during the development of T2DM and cancer, the present review focuses on molecular aspects of antidiabetic and anticancer activities of MLT and, moreover, discusses several future directions of research regarding MLT application as potential therapeutic agent.

Methods: Critical literature analysis in PubMed central combined with personal expertise.

Results: Numerous in vitro and in vivo studies have revealed that MLT possesses a number of antidiabetic health benefits by diminishing hyperglycemia, insulin resistance, oxidative stress, and inflammation through modulating various intracellular signaling pathways or other targets involved in the pathophysiology of this disease. Mounting evidence also indicates that MLT exhibits multi-targeted anticancer effects in numerous human malignancies, mainly resulting from its ability to modulate several signal transduction pathways associated with cell survival, proliferation, and apoptosis. Furthermore, beneficial synergistic action of MLT with chemotherapy and radiotherapy has also been observed. Importantly, no adverse outcomes have been found from the clinical use of MLT, which highlights its therapeutic usefulness, either alone or in combination with other conventional therapies, in cancer treatment.

Conclusion: The findings described in this review suggest that MLT may confer potential benefits to human health, particularly in respect to T2DM and cancer.
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http://dx.doi.org/10.2174/0929867324666170718110606DOI Listing
November 2017

Comparison of leukocyte IL6 expression in patients with gestational diabetes mellitus (GDM) diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria.

Endokrynol Pol 2017 29;68(3):317-325. Epub 2017 Mar 29.

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University, Lodz, Poland.

Introduction: Controversial data exist in the literature regarding relationship of IL-6 with gestational diabetes mellitus (GDM), partially resulting from different criteria for GDM classification. In the present study, we revised this linkage by investigating leukocyte IL6 expression and its associations with clinical characteristics of patients diagnosed by the Polish Diabetes Association (PDA) 2011 and 2014 criteria.

Material And Methods: A total of 145 pregnant women underwent 75 g two-hour OGTT, and GDM was diagnosed according to PDA 2011 criteria (GDM/PDA 2011 group; n = 113) and PDA 2014 criteria (GDM/PDA 2014 group; n = 104). IL6 gene expression was investigated in leukocytes of all participants by using real-time PCR method.

Results: Compared to respective NGT control groups, the GDM/PDA 2011 group exhibited higher FPG, two-hour OGTT, HbA1C and IL6 expression and lower HDL-C, whereas the GDM/PDA 2014 group had higher FPG, one-hour and two-hour OGTT, HbA1C and HOMA-IR, lower QUICKI-IS, and unchanged IL6 expression. No differences in metabolic parameters and IL6 expression were found between the two GDM groups. Compared to the NGT/PDA 2011 group, the NGT/PDA 2014 group had lower one-hour and higher two-hour OGTT and increased IL6 expression. With PDA 2014 criteria, IL6 expression correlated positively with two-hour OGTT in both NGT and GDM groups as well as with LDL-C in NGT group, and negatively with HDL-C in NGT group. With PDA 2011 criteria, no associations were evident in NGT and GDM groups. Nevertheless, significant positive correlation of IL6 mRNA with two-hour OGTT was observed in the entire study group.

Conclusions: Differences in metabolic phenotypes as well as gene expression and correlation data between GDM and NGT groups, categorised based on PDA 2011 and 2014 criteria, are related to changes in gestational glucose tolerance status resulting from using PDA 2014 criteria. Moreover, our findings support the hypothesis that IL-6 is associated with glucose metabolism during pregnancy.
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http://dx.doi.org/10.5603/EP.a2017.0014DOI Listing
December 2017

Increased expression of immune-related genes in leukocytes of patients with diagnosed gestational diabetes mellitus (GDM).

Exp Biol Med (Maywood) 2016 Mar 13;241(5):457-65. Epub 2015 Nov 13.

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, 90-752 Lodz, Poland.

Compelling evidence indicates that the immune system is linked to metabolism in gestational diabetes mellitus (GDM), but factors participating in these processes still are awaiting identification. Inducible nitric oxide synthase, encoded by the NOS2 gene, and surfactant protein D, encoded by the SFTPD gene, have been implicated in diabetes. We investigated NOS2 and SFTPD mRNA levels in leukocytes obtained from 125 pregnant women with (n = 87) or without (control group; n = 38) GDM, and, in turn, correlated their expression with clinical parameters of subjects. Leukocytes were isolated from the blood of pregnant women and NOS2 and SFTPD expression in these cells was determined by quantitative real time PCR (qRT-PCR). Univariate correlation analyses were performed to assess an association between leukocyte NOS2 and SFTPD expression and clinical characteristics of patients. qRT-PCR experiments disclosed significantly increased leukocyte NOS2 and SFTPD mRNA levels in hyperglycemic GDM patients (P < 0.05). In the entire study group, there were significant positive associations of leukocyte NOS2 and SFTPD mRNAs with C-reactive protein. Additionally, transcript level of SFTPD also correlated positively with fasting glycemia and insulin resistance. This study demonstrates that an impaired glucose metabolism in GDM may be predominant predictor of leukocyte NOS2 and SFTPD overexpression in diabetic patients. Furthermore, alterations in the expression of these genes are associated with glucose metabolism dysfunction and/or inflammation during pregnancy. In addition, these findings support the utilization of leukocytes as good experimental model to study a relationship between immune-related genes and metabolic changes in women with GDM, as well as to assess the potential mechanisms underlying these alterations.
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http://dx.doi.org/10.1177/1535370215615699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4950477PMC
March 2016

Family, anthropometric and biochemical factors affecting birth weight of infants born to GDM women.

Ginekol Pol 2015 Jul;86(7):499-503

Objectives: Gestational diabetes mellitus (GDM) affects up to 25% of all pregnancies worldwide. If untreated, GDM leads to increased complication rates both, in the mother and the fetus. Early diagnosis and adequate management of GDM are essential to avoid macrosomia. Nonetheless, neonates born to GDM mothers often have high birth weight. The aim of the study was to evaluate selected factors which can affect neonatal birth weight.

Material And Methods: The study included 152 women with GDM and 58 healthy pregnant controls. Anthropometric data of both parents, maternal biochemical parameters, and neonatal birth weight were collected.

Results: The independent factors influencing neonatal birth weight were pregnancy duration, maternal smoking, as well as birth weight and current weight of the father. The risk of delivering a large for gestational age (LGA) infant increases with the diagnosis of GDM, higher maternal pre-pregnancy weight, and higher fasting glycaemia. No correlation between maternal fasting glycaemia, HbA1c, 1,5-AG, lipids and neonatal birth weight was found.

Conclusions: Risk factors for LGA include gestational diabetes, high maternal pre-pregnancy weight, and current body weight of the father. Neither HbA1c nor 1,5-AG were reliable predictors of neonatal birth weight and occurrence of LGA in the studied population.
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http://dx.doi.org/10.17772/gp/652DOI Listing
July 2015

Gestational diabetes mellitus is associated with increased leukocyte peroxisome proliferator-activated receptor γ expression.

Arch Med Sci 2015 Aug 14;11(4):779-87. Epub 2015 Jan 14.

Polish Mother's Memorial Hospital, Research Institute, Lodz, Poland ; Diabetology and Metabolic Diseases Department, Medical University of Lodz, Lodz, Poland.

Introduction: Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor of the nuclear receptor superfamily that is involved in lipid and carbohydrate metabolism as well as inflammation; thereby it participates in metabolic diseases including diabetes. Although PPARγ expression has been observed in different tissues of diabetic patients, its level in leukocytes from subjects affected by gestational diabetes mellitus (GDM) has not yet been reported. This study aimed to investigate leukocyte PPARG expression in GDM patients at 24-33 weeks of gestation and, in turn, to correlate these alterations with anthropometric and metabolic parameters of patients.

Material And Methods: Leukocytes were isolated from the blood of normal glucose tolerant (NGT; n = 34) and GDM (n = 77) pregnant women between 24 and 33 weeks of gestation. Leukocyte PPARG mRNA expression was determined by semi-quantitative polymerase chain reaction. Univariate correlation analysis was performed to investigate associations between PPARG expression and clinical characteristics of patients.

Results: Leukocyte PPARG mRNA level was significantly higher in GDM than NGT women (p < 0.05). In the whole study group, PPARG expression positively correlated with plasma glucose concentrations at 1 h (r = 0.222, p = 0.049) and 2 h (r = 0.315, p = 0.020) of 75 g oral glucose tolerance test (OGTT), and negatively correlated with plasma HDL cholesterol concentration (r = -0.351, p = 0.010).

Conclusions: The correlation between leukocyte PPARG overexpression and hyperglycaemia suggests that PPARG mRNA expression in these cells might be up-regulated in high-glucose conditions in GDM patients at 24-33 weeks of gestation.
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http://dx.doi.org/10.5114/aoms.2015.47692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4548020PMC
August 2015

Dual stimulus-dependent effect of Oenothera paradoxa extract on the respiratory burst in human leukocytes: suppressing for Escherichia coli and phorbol myristate acetate and stimulating for formyl-methionyl-leucyl-phenylalanine.

Oxid Med Cell Longev 2014 14;2014:764367. Epub 2014 Sep 14.

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland.

Although a growing body of evidence suggests that plant polyphenols can modulate human immune responses, their simultaneous action on monocyte and neutrophil oxidative burst is currently poorly understood. Based on the hypothesis that various polyphenols contained in plant extracts might affect the oxidative burst of phagocytes, we evaluated the effects of ethanolic O. paradoxa extract polyphenols on monocyte and neutrophil oxidative burst in vitro activated by different stimuli, including opsonized bacteria E. coli, phorbol 12-myristate 13-acetate (PMA), and formyl-methionyl-leucyl-phenylalanine (fMLP). Samples were analyzed by the dihydrorhodamine flow cytometry assay. Our results showed that the extract repressed significantly and dose-dependently reactive oxygen species production in both cell types stimulated with E. coli and PMA (P < 0.05) and its inhibitory efficiency was stimulus- and cell-type-dependent. Interestingly, there was significant stimulatory effect of the extract on bursting phagocytes induced by fMLP (P < 0.05). Additionally, several flavonoids and phenolic compounds as well as penta-galloyl-β-(D)-glucose (PGG), the representative of hydrolyzable tannins, were identified in the 60% extract by high-performance liquid chromatography (HPLC) coupled to electrospray ionization in negative ion mode. In summary, the ethanolic O. paradoxa extract, rich in flavonoids and phenolic compounds, exhibits dual stimulus-dependent effect on the respiratory burst in human leukocytes; hence, it might affect immune responses in humans.
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http://dx.doi.org/10.1155/2014/764367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178919PMC
June 2015

The relationship between adipose tissue-derived hormones and gestational diabetes mellitus (GDM).

Endokrynol Pol 2014 ;65(2):134-42

Gestational diabetes mellitus (GDM) is defined as a glucose intolerance of varying severity with onset or first recognition during pregnancy. The prevalence of GDM is growing rapidly worldwide, resulting in numerous and serious complications for both mother and foetus. Two major metabolic disorders, insulin resistance and β cells dysfunction, are currently linked to the pathogenesis of GDM, although the cellular mechanisms involved in the development of GDM are not yet completely understood. Increasing evidence from clinical and experimental studies indicates that adipose tissue dysfunction, characterised by abnormal production of adipokines, is an essential factor linked to insulin resistance and GDM. To date, several adipose tissue-derived hormones have been identified, including leptin, adiponectin, resistin, visfatin, apelin, retinol-binding protein 4 (RBP-4), vaspin, and omentin. The relationship of leptin and adiponectin to insulin resistance in GDM is relatively well documented, but the molecular mechanisms by which these hormones affect insulin resistance are not yet fully known. The other aforementioned adipokines appear to be also important players in the pathophysiology of GDM, although their precise function in this complex process remains to be established. The aim of this article is to review the literature concerning the relationship between the above-mentioned adipokines and GDM, and to clarify their role in the pathophysiology of GDM.
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http://dx.doi.org/10.5603/EP.2014.0019DOI Listing
December 2015

The association of leukocyte phosphatidylinositol 3-kinase delta overexpression with gestational diabetes mellitus (GDM).

Endokrynol Pol 2014 ;65(1):17-24

Introduction: An increasing body of evidence has linked diabetes to inflammation. The phosphatidylinositol 3-kinase delta (PI3-K delta), a member of the PI3K class IA family, has been implicated in the regulation of inflammation since it is predominantly expressed in leukocytes. To date, no information has been available on the relationship of leukocyte PI3-K delta with gestational diabetes mellitus (GDM). Therefore, the aim of this study was to investigate changes in leukocyte PIK3CD mRNA expression in GDM women and, in turn, to correlate them with anthropometric and metabolic parameters of patients. Additionally, an association between leukocyte mRNA expression of PIK3CD and Sirtuin 1 (SIRT1) was determined.

Material And Methods: Blood samples from women with normal glucose tolerance (NGT; n = 43) and GDM (n = 132) at 24-33 weeks of gestation were collected. After isolating leukocytes from the blood, quantitative real time PCR (qRT-PCR) was performed to determine PIK3CD gene expression in these cells. Univariate regression analyses were used to assess an association of leukocyte PIK3CD mRNA level with clinical characteristics of patients as well as with leukocyte SIRT1 mRNA expression.

Results: Leukocyte PIK3CD mRNA was increased by 1.98-fold in the GDM v. NGT subjects and inversely correlated with low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) in diabetic pregnancy. There were also significant positive correlations of leukocyte PIK3CD mRNA with plasma glucose concentration at 2h of 75 g oral glucose tolerance test (OGTT) and SIRT1 mRNA in the whole study population (both P < 0.05).

Conclusions: GDM is accompanied by leukocyte PIK3CD overexpression associated with reduced plasma LDL-C and TC levels, as well as with hyperglycaemia and elevated leukocyte SIRT1 mRNA.
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http://dx.doi.org/10.5603/EP.2014.0003DOI Listing
October 2015

[The role of peroxisome proliferator-activated receptors γ (PPARγ) in obesity and insulin resistance].

Postepy Hig Med Dosw (Online) 2013 Dec 11;67:1283-99. Epub 2013 Dec 11.

Zakład Biologii Strukturalnej, Uniwersytet Medyczny w Łodzi.

Obesity, defined as abnormal or excessive fat accumulation, is currently believed to be a major public health problem worldwide. Over the past 20 years, the prevalence of obesity has increased rapidly in both industrialized and developing countries, resulting in a considerably increased risk of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Although the exact pathophysiological mechanisms underlying these diseases remain unclear, clinical and epidemiological studies support the existence of a relationship between obesity-induced inflammation and insulin resistance linked with the development and progression of metabolic diseases. Adipokines, produced and released by adipose tissue, are considered as factors linking obesity-induced inflammation with insulin resistance, and their regulation through peroxisome proliferator-activated receptors γ (PPARγ also known as NR1C3) is essential in these processes. PPARγ are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily which directly regulate the expression of a large number of genes involved in adipocyte differentiation, lipid and carbohydrate metabolism as well as adipokine synthesis; thereby they are implicated in various metabolic disorders, including obesity, insulin resistance, dyslipidemia, and hypertension. This review summarizes the current literature on a functional relationship of PPARγ with obesity and insulin resistance and, moreover, highlights the significance of synthetic ligands of these receptors in the mentioned metabolic disorders.
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http://dx.doi.org/10.5604/17322693.1080028DOI Listing
December 2013

The elevated gene expression level of the A(2B) adenosine receptor is associated with hyperglycemia in women with gestational diabetes mellitus.

Diabetes Metab Res Rev 2014 Jan;30(1):42-53

Department of Structural Biology, Faculty of Biomedical Sciences and Postgraduate Education, Medical University of Lodz, Zeligowskiego 7/9 St., 90-752, Lodz, Poland.

Background: Adenosine receptors denoted by A1 , A2A , A2B , and A3 and encoded by ADORA1, ADORA2A, ADORA2B, and ADORA3 genes, respectively, are adenosine-activated G-protein-coupled receptors that play an important role in obesity and type 2 diabetes mellitus. However, little is known about their significance in gestational diabetes mellitus (GDM). The purpose of this study was to investigate whether there are changes in leukocyte AR expression in GDM patients and whether these alterations are linked to well-known diabetic genes.

Methods: Leukocytes were isolated from the blood of normal glucose tolerant (NGT; n = 35) and GDM (n = 82) pregnant women, and expression of ARs was determined by a semi-quantitative polymerase chain reaction (PCR). Univariate correlation analysis was performed to investigate associations between expression of ARs and anthropometric and metabolic parameters of patients. Furthermore, the identification of diabetic genes linked to significantly differentiated leukocyte adenosine receptors expression in GDM women was also carried out with the use of the human diabetes RT(2) profiler PCR arrays.

Results: ADORA2B mRNA expression was significantly higher in GDM versus NGT pregnant women (p < 0.05), and positively correlated with the glucose level at 1-h 75-g oral glucose tolerance test (OGTT; r = 0.21, p = 0.044). Nineteen diabetic genes linked to leukocyte ADORA2B overexpression associated with hyperglycemia in GDM women were also identified.

Conclusions: Maternal leukocyte ADORA2B overexpression is associated with hyperglycemia in GDM subjects, and it is accompanied by complex alterations in the expression of diabetes-related genes involved in insulin action, carbohydrate and lipid metabolism, oxidative stress, and inflammation.
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http://dx.doi.org/10.1002/dmrr.2446DOI Listing
January 2014

Adenosine receptors expression is elevated in leukocytes of gestational diabetes mellitus (GDM) subjects--a preliminary study.

Endokrynol Pol 2012 ;63(2):110-4

Department of Structural Biology, Medical University of Lodz, Lodz, Poland.

Introduction: Adenosine receptors (ARs), belonging to the G-protein-coupled receptors (GPCRs), are present in the majority of human cells and tissues. Depending on their biochemical and pharmacologic properties, four subtypes of ARs (i.e. A₁, A(2A), A(2B), and A₃) have been distinguished. Currently, these receptors are attractive molecular targets for pharmacological interventions in various diseases, including diabetes. The literature published to date has shown an altered expression of ARs in several types of cells under diabetic conditions. However, there has been no publication devoted to the investigation of ARs expression in leukocytes of subjects with gestational diabetes mellitus (GDM). Therefore, this study was aimed to determine the expression level of AR subtypes in leukocytes of GDM patients and its relationship to anthropometric and biochemical parameters.

Material And Methods: Gene expression of four AR subtypes in leukocytes of both healthy (n = 34) and GDM (n = 67) subjects in the third trimester of pregnancy (from 24 to 33 weeks) was investigated. Multiple regression analyses were used to assess the association between the expression level of ARs and both anthropometric and biochemical parameters.

Results: Statistically significant (p < 0.05) higher levels of A(2A) and A(2B) mRNAs were observed in leukocytes of the GDM subjects compared to the control group. There was a positive correlation of A(2B) mRNA level with glucose concentration at 120 min of oral glucose tolerance test (OGTT) (r = 0.24, p = 0.041).

Conclusions: Overexpression of A2BAR in leukocytes of the GDM subjects and, additionally, the existence of a relationship between its elevated expression level in these cells and abnormal values of glucose concentration at 120 min of OGTT for GDM, suggest that this subtype might be involved in the pathogenesis of GDM.
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August 2012

New insight into A₁ adenosine receptors in diabetes treatment.

Curr Pharm Des 2010 ;16(38):4237-42

Department of Structural Biology, Medical University of Lodz, 7/9 Zeligowskiego St., 90-752 Lodz, Poland.

The A₁ adenosine receptors (A₁AR), belonging to the rhodopsin-like superfamily of the G-protein-coupled receptors (GPCRs), may regulate many various cellular processes in cardiovascular, renal, and central nervous systems. In addition, since A(1)AR possesses antilipolytic properties, numerous A₁AR agonists and antagonists have been developed, but only some of them with the most promising selective properties in vitro have been advanced to animal studies and clinical trials. In this review, we have summarized the studies on the utility of A₁AR selective agonists and antagonists in the regulation of lipid and carbohydrate metabolism and their potential therapeutic applications in diabetes.
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http://dx.doi.org/10.2174/138161210794519066DOI Listing
July 2011

The effect of divalent cations on the catalytic activity of the human plasma 3'-exonuclease.

Biometals 2010 Dec 30;23(6):1113-21. Epub 2010 Jun 30.

Department of Structural Biology, Medical University of Łódź, 7/9 Żeligowskiego St, 90-752, Lodz, Poland.

The 3'-exonuclease from human plasma is a soluble form of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) (EC 3.1.4.1/EC 3.6.1.9). Here, the possibility of divalent cation influence for the 3'-exonuclease activity was investigated using the phosphorothioate congener of oligonucleotide containing all phosphorothioate internucleotide linkages of the [R(P)]-configuration ([R(P)-PS]-d[T(12)]) as the substrate for this enzyme. It was found that the 3'-exonuclease is a metalloenzyme, i.e. its phosphodiesterase activity was completely abolished at 0.8 mM concentration EDTA and, in turn, it was restored in the presence of Mg(2+) or Mn(2+) ions. In addition, Mg(2+) can be replaced effectively by Ca(2+), Mn(2+), or Co(2+), but not by Ni(2+) and Cd(2+) during the hydrolysis of the phosphorothioate substrate in human plasma. In addition, the mechanism is postulated, by which a single internucleotide phosphorothioate bond of the S(P)-configuration at the 3'-end of unmodified phosphodiesters (PO-oligos), or their phosporothioate analogs (PS-oligos) protects these compounds against degradation in blood.
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http://dx.doi.org/10.1007/s10534-010-9358-5DOI Listing
December 2010

Structure and physiological functions of the human peroxisome proliferator-activated receptor gamma.

Arch Immunol Ther Exp (Warsz) 2008 Sep-Oct;56(5):331-45

Department of Structural Biology, Chair of General Endocrinology, Medical University of Łódź, Zeligowskiego 7/9, 90-752, Łódź, Poland.

The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily. To date, three different PPAR isotypes, namely PPAR-alpha, -delta, and -gamma, have been identified in vertebrates and have distinct patterns of tissue distribution. Like all nuclear receptors, the human PPAR-gamma (hPPAR-gamma) is characterized by a modular structure composed of an N-terminal A/B domain, a DNA-binding domain with two zinc fingers (C domain), a D domain, and a C-terminal ligand-binding domain (E/F domain). Human PPAR-gamma exists in two protein isoforms, hPPAR-gamma(1) and -gamma(2), with different lengths of the N-terminal. The hPPAR-gamma(2) isoform is predominantly expressed in adipose tissue, whereas hPPAR-gamma(1) is relatively widely expressed. Human PPAR-gamma plays a critical physiological role as a central transcriptional regulator of both adipogenic and lipogenic programs. Its transcriptional activity is induced by the binding of endogenous and synthetic lipophilic ligands, which has led to the determination of many roles for PPAR-gamma in pathological states such as type 2 diabetes, atherosclerosis, inflammation, and cancer. Of the synthetic ligands, the thiazolidinedione class of insulin-sensitizing drugs (ciglitazone, pioglitazone, troglitazone, rosiglitazone) is employed clinically in patients with type 2 diabetes.
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http://dx.doi.org/10.1007/s00005-008-0037-yDOI Listing
January 2009

[Clinical and molecular characterization of gastrointestinal stromal tumors (GIST)].

Postepy Hig Med Dosw (Online) 2007 Jun 9;62:272-81. Epub 2007 Jun 9.

Zakład Biologii Strukturalnej, Katedra Endokrynologii Ogólnej, Uniwersytet Medyczny w Łodzi.

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors of the gastrointestinal tract, the diagnosis of which is difficult. The presence of membrane receptor c-KIT on GIST cells implies their origin from a precursor of interstitial cells of Cajal. Mutations in the c-kit gene result in the constitutive ligand-independent activation of the c-KIT receptor and, consequently, aberrant cell division and tumor growth. Imatinib (STI571), used in the treatment of unresectable GIST, selectively inhibits the enzymatic activity of the tyrosine kinase c-KIT. However, it is known that some mutations in the c-kit gene lead to resistance to imatinib. Therefore, the search for new effective agents is being continued. In this paper the clinical and molecular characterization of the GIST is presented as well as data related to imatinib in the treatment of GIST. Moreover, novel agents for the treatment of patients with advanced GIST are described.
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June 2007

Nicotinamide riboside kinase structures reveal new pathways to NAD+.

PLoS Biol 2007 Oct;5(10):e263

Structural Genomics Consortium and Department of Pharmacology, University of Toronto, Toronto, Canada.

The eukaryotic nicotinamide riboside kinase (Nrk) pathway, which is induced in response to nerve damage and promotes replicative life span in yeast, converts nicotinamide riboside to nicotinamide adenine dinucleotide (NAD+) by phosphorylation and adenylylation. Crystal structures of human Nrk1 bound to nucleoside and nucleotide substrates and products revealed an enzyme structurally similar to Rossmann fold metabolite kinases and allowed the identification of active site residues, which were shown to be essential for human Nrk1 and Nrk2 activity in vivo. Although the structures account for the 500-fold discrimination between nicotinamide riboside and pyrimidine nucleosides, no enzyme feature was identified to recognize the distinctive carboxamide group of nicotinamide riboside. Indeed, nicotinic acid riboside is a specific substrate of human Nrk enzymes and is utilized in yeast in a novel biosynthetic pathway that depends on Nrk and NAD+ synthetase. Additionally, nicotinic acid riboside is utilized in vivo by Urh1, Pnp1, and Preiss-Handler salvage. Thus, crystal structures of Nrk1 led to the identification of new pathways to NAD+.
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http://dx.doi.org/10.1371/journal.pbio.0050263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1994991PMC
October 2007

Nucleotide pyrophosphatase/phosphodiesterase 1 is responsible for degradation of antisense phosphorothioate oligonucleotides.

Oligonucleotides 2007 ;17(1):134-45

Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Łódź, Poland.

The rapid degradation of unmodified phosphodiester oligodeoxynucleotides (PO-oligos) by exo -and endonucleases limits their application as antisense constructs and requires the synthesis and use of modified oligonucleotides. Phosphorothioate analogs of oligonucleotides (PS-oligos) are much more stable against nucleolytic degradation than their unmodified counterparts, and this is one of the reasons for which they are a promising class of antisense oligonucleotides. However, PS-oligos also undergo slow hydrolysis by enzymes present in plasma. The oligonucleotide degradation proceeds mainly from the 3' -end, resulting in the formation of a typical ladder of shorter products and the release of the mononucleoside 5' -phosphorothioates. So far, little has been known concerning the molecular identity of the enzymes involved in the degradation of PS-oligos. We now identify the human plasma 3' -exonuclease responsible for their degradation as a soluble form of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) (EC 3.1.4.1/EC 3.6.1.9), also known as the plasma cell differentiation antigen PC-1. We also show that adenosine or deoxyadenosine (alpha-thio)triphosphates can act as potent inhibitors of NPPs.
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http://dx.doi.org/10.1089/oli.2007.0021DOI Listing
June 2007

Mapping of the functional phosphate groups in the catalytic core of deoxyribozyme 10-23.

FEBS J 2007 Feb 22;274(4):1062-72. Epub 2007 Jan 22.

Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies of the Polish Academy of Sciences, Lodz, Poland.

The RNA phosphodiester bond cleavage activity of a series of 16 thio-deoxyribozymes 10-23, containing a P-stereorandom single phosphorothioate linkage in predetermined positions of the catalytic core from P1 to P16, was evaluated under single-turnover conditions in the presence of either 3 mM Mg(2+) or 3 mM Mn(2+). A metal-specificity switch approach permitted the identification of nonbridging phosphate oxygens (proR(P) or proS(P)) located at seven positions of the core (P2, P4 and P9-13) involved in direct coordination with a divalent metal ion(s). By contrast, phosphorothioates at positions P3, P6, P7 and P14-16 displayed no functional relevance in the deoxyribozyme-mediated catalysis. Interestingly, phosphorothioate modifications at positions P1 or P8 enhanced the catalytic efficiency of the enzyme. Among the tested deoxyribozymes, thio-substitution at position P5 had the largest deleterious effect on the catalytic rate in the presence of Mg(2+), and this was reversed in the presence of Mn(2+). Further experiments with thio-deoxyribozymes of stereodefined P-chirality suggested direct involvement of both oxygens of the P5 phosphate and the proR(P) oxygen at P9 in the metal ion coordination. In addition, it was found that the oxygen atom at C6 of G(6) contributes to metal ion binding and that this interaction is essential for 10-23 deoxyribozyme catalytic activity.
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http://dx.doi.org/10.1111/j.1742-4658.2007.05655.xDOI Listing
February 2007

Glutamine-dependent NAD+ synthetase. How a two-domain, three-substrate enzyme avoids waste.

J Biol Chem 2006 Nov 5;281(44):33395-402. Epub 2006 Sep 5.

Department of Genetics and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.

Glutamine-dependent NAD(+) synthetase, Qns1, utilizes a glutamine aminotransferase domain to supply ammonia for amidation of nicotinic acid adenine dinucleotide (NaAD(+)) to NAD(+). Earlier characterization of Qns1 suggested that glutamine consumption exceeds NAD(+) production by 40%. To explore whether Qns1 is systematically wasteful or whether additional features account for this behavior, we performed a careful kinetic and molecular genetic analysis. In fact, Qns1 possesses remarkable properties to reduce waste. The glutaminase active site is stimulated by NaAD(+) more than 50-fold such that glutamine is not appreciably consumed in the absence of NaAD(+). Glutamine consumption exceeds NAD(+) production over the whole range of glutamine and NaAD(+) substrate concentrations with greatest efficiency occurring at saturation of both substrates. Kinetic data coupled with site-directed mutagenesis of amino acids in the predicted ammonia channel indicate that NaAD(+) stimulates the glutaminase active site in the k(cat) term by a synergistic mechanism that does not require ammonia utilization by the NaAD(+) substrate. Six distinct classes of Qns1 mutants that fall within the glutaminase domain and the synthetase domain selectively inhibit components of the coordinated reaction.
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http://dx.doi.org/10.1074/jbc.M607111200DOI Listing
November 2006

Synthetic lethal and biochemical analyses of NAD and NADH kinases in Saccharomyces cerevisiae establish separation of cellular functions.

J Biol Chem 2006 Aug 7;281(32):22439-45. Epub 2006 Jun 7.

Department of Genetics and Biochemistry and Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.

Production of NADP and NADPH depends on activity of NAD and NADH kinases. Here we characterized all combinations of mutants in yeast NAD and NADH kinases to determine their physiological roles. We constructed a diploid strain heterozygous for disruption of POS5, encoding mitochondrial NADH kinase, UTR1, cytosolic NAD kinase, and YEF1, a UTR1-homologous gene we characterized as encoding a low specific activity cytosolic NAD kinase. pos5 utr1 is a synthetic lethal combination rescued by plasmid-borne copies of the POS5 or UTR1 genes or by YEF1 driven by the ADH1 promoter. Respiratory-deficient and oxidative damage-sensitive defects in pos5 mutants were not made more deleterious by yef1 deletion, and a quantitative growth phenotype of pos5 and its arginine auxotrophy were repaired by plasmid-borne POS5 but not UTR1 or ADH1-driven YEF1. utr1 haploids have a slow growth phenotype on glucose not exacerbated by yef1 deletion but reversed by either plasmid-borne UTR1 or ADH1-driven YEF1. The defect in fermentative growth of utr1 mutants renders POS5 but not POS5-dependent mitochondrial genome maintenance essential because rho-utr1 derivatives are viable. Purified Yef1 has similar nucleoside triphosphate specificity but substantially lower specific activity and less discrimination in favor of NAD versus NADH phosphorylation than Utr1. Low expression and low intrinsic NAD kinase activity of Yef1 and the lack of phenotype associated with yef1 suggest that Utr1 and Pos5 are responsible for essentially all NAD/NADH kinase activity in vivo. The data are compatible with a model in which there is no exchange of NADP, NADPH, or cytoplasmic NAD/NADH kinase between nucleocytoplasmic and mitochondrial compartments, but the cytoplasm is exposed to mitochondrial NAD/NADH kinase during the transit of the molecule.
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http://dx.doi.org/10.1074/jbc.M513919200DOI Listing
August 2006

A novel class of DNA analogs bearing 5'-C-phosphonothymidine units: synthesis and physicochemical and biochemical properties.

Oligonucleotides 2006 ;16(1):68-82

Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies of Polish Academy of Sciences, 90-363 Lodz, Poland.

S(C) and R(C) diastereomers of 5'-C-(O,O-diethyl)-phosphonylthymidine ((R)T and (S)T) were used for the synthesis of the dimers T(R)T and T(S)T, respectively. These dimers were incorporated at selected sites in oligonucleotide constructs. Melting temperature (Tm) experiments demonstrated that relative to the unmodified oligodeoxyribonucleotide, the presence of the (R)T moiety reduced the thermal stability of the duplexes by approximately 5.0 degrees C per modification, whereas their (S)T counterparts only slightly destabilized the duplex structure (deltaTm < or = 1 degree C/modification). The stability of the triple-helical complexes containing one, two, or three modified thymidines is slightly higher than that of the parent complex. Nuclease resistance studies performed with snake venom phosphodiesterase, calf spleen phosphodiesterase, and 3'-exonuclease from human plasma showed that cleavage of the oligonucleotides at the site of the modification was completely suppressed regardless of the stereochemistry of the 5'-C-chiral center. The influence of the (R)T and (S)T modification in the recognition sequence of HindIII, EcoRI, and HpaI restriction endonucleases was also investigated. Although the catalytic activity of HindIII was not affected by the presence of the 5'-C-ethoxyphosphonyl modification, the activities of the two remaining restriction enzymes were partially suppressed depending on the site of modification or the stereochemistry of the modification or both ((R)T vs. (S)T).
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http://dx.doi.org/10.1089/oli.2006.16.68DOI Listing
June 2006

[Structure, mode of action and biological role of ecto-nucleotide pyrophosphatase/phosphodiesterase enzyme family].

Postepy Biochem 2003 ;49(3):202-12

Polska Akademia Nauk, Centrum Badań Molekularnych i Makromolekularnych, Zakład Chemii Bioorganicznej, ul. Sienkiewicza 112, 90-363 Łódź.

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June 2004

Retention of configuration in the action of human plasma 3'-exonuclease on oligo(deoxynucleoside phosphorothioate). A new method for assignment of absolute configuration at phosphorus in isotopomeric deoxyadenosine 5'-O-[(18)O]phosphorothioate.

J Am Chem Soc 2002 May;124(17):4623-7

Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland.

A new method of analysis has allowed the exonucleolytic cleavage by human 3'-exonuclease to be determined. Hydrolysis by human plasma 3'-exonuclease proceeds with retention of configuration at phosphorus. The new method determines the sense of chirality at phosphorus in isotopomeric adenosine 5'-O-[(18)O]phosphorothioates. This is based on stereospecific two-step conversion of the mono-thionucleotide into the corresponding deoxyadenosine 5'-O-alpha-[(18)O]thiotriphosphate, followed by the use of terminal deoxyribonucleotidyl transferase and MALDI TOF mass spectrometry of the resulting elongated primer. Retention of configuration in the reaction of plasma 3'-exonuclease implies a two-step mechanism with two displacements on phosphorus. Inversion at each step leads to overall retention.
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http://dx.doi.org/10.1021/ja017187uDOI Listing
May 2002