Publications by authors named "Andrzej Zieleniak"

10 Publications

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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

Visceral Adipose Tissue of Prediabetic and Diabetic Females Shares a Set of Similarly Upregulated microRNAs Functionally Annotated to Inflammation, Oxidative Stress and Insulin Signaling.

Antioxidants (Basel) 2021 Jan 12;10(1). Epub 2021 Jan 12.

Department of Nucleic Acid Biochemistry, Medical University of Lodz, 92-213 Lodz, Poland.

Hypertrophic and hypoxic visceral adipose tissue (VAT) secretes proinflammatory cytokines promoting insulin resistance (IR), prediabetes and type 2 diabetes (T2DM) microRNAs (miRNAs) are markers of metabolic disorders regulating genes critical for e.g., inflammation, glucose metabolism, and antioxidant defense, with raising diagnostic value. The aim of the current study was to evaluate whether hyperglycemia is able to affect the expression of selected miRNAs in VAT of prediabetic (IFG) and diabetic (T2DM) patients vs. normoglycemic (NG) subjects using qPCR. Statistical analyses suggested that miRNAs expression could be sex-dependent. Thus, we determined 15 miRNAs as differentially expressed (DE) among NG, T2DM, IFG females (miR-10a-5p, let-7d-5p, miR-532-5p, miR-127-3p, miR-125b-5p, let-7a-5p, let-7e-5p, miR-199a-3p, miR-365a-3p, miR-99a-5p, miR-100-5p, miR-342-3p, miR-146b-5p, miR-204-5p, miR-409-3p). Majority of significantly changed miRNAs was similarly upregulated in VAT of female T2DM and IFG patients in comparison to NG subjects, positively correlated with FPG and HbA1c, yet, uncorrelated with WHR/BMI. Enrichment analyses indicated involvement of 11 top DE miRNAs in oxidative stress, inflammation and insulin signaling. Those miRNAs expression changes could be possibly associated with low-grade chronic inflammation and oxidative stress in VAT of hyperglycemic subjects.
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http://dx.doi.org/10.3390/antiox10010101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828194PMC
January 2021

Associations of Arginine with Gestational Diabetes Mellitus in a Follow-Up Study.

Int J Mol Sci 2020 Oct 22;21(21). Epub 2020 Oct 22.

Chair of Medical Biology, Laboratory of Metabolomic Studies, Department of Structural Biology, Faculty of Medicine Department of Biomedical Sciences, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland.

In the reported study we applied the targeted metabolomic profiling employing high pressure liquid chromatography coupled with triple quadrupole tandem mass spectrometry (HPLC-MS/MS) to understand the pathophysiology of gestational diabetes mellitus (GDM), early identification of women who are at risk of developing GDM, and the differences in recovery postpartum between these women and normoglycemic women. We profiled the peripheral blood from patients during the second trimester of pregnancy and three months, and one year postpartum. In the GDM group Arg, Gln, His, Met, Phe and Ser were downregulated with statistical significance in comparison to normoglycemic (NGT) women. From the analysis of the association of all amino acid profiles of GDM and NGT women, several statistical models predicting diabetic status were formulated and compared with the literature, with the arginine-based model as the most promising of the screened ones (area under the curve (AUC) = 0.749). Our research results have shed light on the critical role of arginine in the development of GDM and may help in precisely distinguishing between GDM and NGT and earlier detection of GDM but also in predicting women with the increased type 2 diabetes mellitus (T2DM) risk.
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http://dx.doi.org/10.3390/ijms21217811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7659483PMC
October 2020

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

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

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

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