Publications by authors named "Jacek Kasznicki"

25 Publications

  • Page 1 of 1

A potential role of calpains in sulfonylureas (SUs) -mediated death of human pancreatic cancer cells (1.2B4).

Toxicol In Vitro 2021 Feb 27;73:105128. Epub 2021 Feb 27.

Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska, 92-213 Lodz, Poland. Electronic address:

Sulfonylureas (SUs) are suggested to accelerate the pancreatic β-cells mass loss via apoptosis. However, little is known whether calpains mediate this process. The aim of the present study is to evaluate the involvement of calpains in SUs-induced death of human pancreatic cancer (PC) cell line 1.2B4. The cells were exposed to: glibenclamide, glimepiride and gliclazide for 72 h. The expression analysis of caspase-3 (CASP-3), TP53, calpain 1 (CAPN-1), calpain 2 (CAPN-2) and calpain 10 (CAPN-10) was detected using RT-PCR method. Intracellular Ca concentrations, CASP-3 activity and total calpain activity were also evaluated. Our results have shown that glibenclamide and glimepiride decrease 1.2B4 cells viability with accompanied increase in intracellular Ca concentration and increased expression of apoptosis-related CASP-3 and TP53. Gliclazide did not affect 1.2B4 cell viability and Ca concentration, however, it downregulated CASP-3 and upregulated TP53. Interestingly, 50 μM glimepiride increased expression of CAPN-1, CAPN-2 and CAPN-10 whereas 50 μM glibenclamide solely upregulated CAPN-2 expression. We have shown that 10 μM and 50 μM glibenclamide and glimepiride increased the activity of CASP-3, but decreased total calpain activity. Our results suggest that calpains may be involved in glibenclamide- and glimepiride-induced death of PC cells. However, further investigation is required to confirm the engagement of calpains in SUs-mediated death of PC cells, especially studies on protein level of particular isoforms of calpains should be conducted.
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http://dx.doi.org/10.1016/j.tiv.2021.105128DOI Listing
February 2021

The Role of microRNAs in Metabolic Syndrome-Related Oxidative Stress.

Int J Mol Sci 2020 Sep 20;21(18). Epub 2020 Sep 20.

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

Oxidative stress (OxS) is the cause and the consequence of metabolic syndrome (MetS), the incidence and economic burden of which is increasing each year. OxS triggers the dysregulation of signaling pathways associated with metabolism and epigenetics, including microRNAs, which are biomarkers of metabolic disorders. In this review, we aimed to summarize the current knowledge regarding the interplay between microRNAs and OxS in MetS and its components. We searched PubMed and Google Scholar to summarize the most relevant studies. Collected data suggested that different sources of OxS (e.g., hyperglycemia, insulin resistance (IR), hyperlipidemia, obesity, proinflammatory cytokines) change the expression of numerous microRNAs in organs involved in the regulation of glucose and lipid metabolism and endothelium. Dysregulated microRNAs either directly or indirectly affect the expression and/or activity of molecules of antioxidative signaling pathways (SIRT1, FOXOs, Keap1/Nrf2) along with effector enzymes (e.g., GPx-1, SOD1/2, HO-1), ROS producers (e.g., NOX4/5), as well as genes of numerous signaling pathways connected with inflammation, insulin sensitivity, and lipid metabolism, thus promoting the progression of metabolic imbalance. MicroRNAs appear to be important epigenetic modifiers in managing the delicate redox balance, mediating either pro- or antioxidant biological impacts. Summarizing, microRNAs may be promising therapeutic targets in ameliorating the repercussions of OxS in MetS.
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http://dx.doi.org/10.3390/ijms21186902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555602PMC
September 2020

Life-threatening Anaemia in Patient with Hereditary Haemorrhagic Telangiectasia (Rendu-Osler-Weber Syndrome).

Open Med (Wars) 2020 6;15:134-138. Epub 2020 Mar 6.

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, 251 Pomorska Street, 92-213 Lodz, Poland.

Hereditary haemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a rare autosomal dominant vascular disorder. Patients with HHT may present with a wide spectrum of clinical manifestations from epistaxis to clinically significant arteriovenous malformations (AVM) in the lungs, liver, brain and spine. The diagnosis of HHT is based on clinical criteria. There is a long diagnostic delay of nearly 3 decades since disease onset. The treatment is based on various types of haemostasis. There is ongoing research with potential therapies which may prevent and decrease the severity of epistaxis. Thalidomide may be an effective treatment to decrease the bleeding symptoms of patients with HHT.
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http://dx.doi.org/10.1515/med-2020-0020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065421PMC
March 2020

Molecular Insight into the Interaction between Epigenetics and Leptin in Metabolic Disorders.

Nutrients 2019 Aug 12;11(8). Epub 2019 Aug 12.

Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland.

Nowadays, it is well-known that the deregulation of epigenetic machinery is a common biological event leading to the development and progression of metabolic disorders. Moreover, the expression level and actions of leptin, a vast adipocytokine regulating energy metabolism, appear to be strongly associated with epigenetics. Therefore, the aim of this review was to summarize the current knowledge of the epigenetic regulation of leptin as well as the leptin-induced epigenetic modifications in metabolic disorders and associated phenomena. The collected data indicated that the deregulation of leptin expression and secretion that occurs during the course of metabolic diseases is underlain by a variation in the level of promoter methylation, the occurrence of histone modifications, along with miRNA interference. Furthermore, leptin was proven to epigenetically regulate several miRNAs and affect the activity of the histone deacetylases. These epigenetic modifications were observed in obesity, gestational diabetes, metabolic syndrome and concerned various molecular processes like glucose metabolism, insulin sensitivity, liver fibrosis, obesity-related carcinogenesis, adipogenesis or fetal/early postnatal programming. Moreover, the circulating miRNA profiles were associated with the plasma leptin level in metabolic syndrome, and miRNAs were found to be involved in hypothalamic leptin sensitivity. In summary, the evidence suggests that leptin is both a target and a mediator of epigenetic changes that develop in numerous tissues during metabolic disorders.
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http://dx.doi.org/10.3390/nu11081872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723573PMC
August 2019

Hyperglycemia Affects miRNAs Expression Pattern during Adipogenesis of Human Visceral Adipocytes-Is Memorization Involved?

Nutrients 2018 Nov 15;10(11). Epub 2018 Nov 15.

Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213, 92-213 Lodz, Poland.

microRNAs are increasingly analyzed in adipogenesis, whose deregulation, especially visceral, contributes to the development of diabetes. Hyperglycemia is known to affect cells while occurring acutely and chronically. Therefore, we aimed to evaluate the effect of hyperglycemia on human visceral pre/adipocytes from the perspective of microRNAs. The relative expression of 78 microRNAs was determined by TaqMan Low Density Arrays at three stages of HPA-v adipogenesis conducted under normoglycemia, chronic, and intermittent hyperglycemia (30 mM). Hierarchical clustering/Pearson correlation revealed the relationship between various microRNAs' expression profiles, while functional analysis identified the genes and signaling pathways regulated by differentially expressed microRNAs. Hyperglycemia affected microRNAs' expression patterns during adipogenesis, and at the stage of pre-adipocytes, differentiated and matured adipocytes compared to normoglycemia. Interestingly, the changes that were evoked upon hyperglycemic exposure during one adipogenesis stage resembled those observed upon chronic hyperglycemia. At least 15 microRNAs were modulated during normoglycemic and/or hyperglycemic adipogenesis and/or upon intermittent/chronic hyperglycemia. Bioinformatics analysis revealed the involvement of these microRNAs in cell cycles, lipid metabolism, ECM⁻receptor interaction, oxidative stress, signaling of insulin, MAPK, TGF-β, p53, and more. The obtained data suggests that visceral pre/adipocytes exposed to chronic/intermittent hyperglycemia develop a microRNAs' expression pattern, which may contribute to further visceral dysfunction, the progression of diabetic phenotype, and diabetic complications possibly involving "epi"-memory.
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http://dx.doi.org/10.3390/nu10111774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266776PMC
November 2018

Tumour protein 53 is linked with type 2 diabetes mellitus.

Indian J Med Res 2017 Aug;146(2):237-243

Department of Internal Disease, Diabetology & Clinical Pharmacology, Lodz, Poland.

Background & Objectives: Tumour protein p53 (TP53) is a stress sensitive transcription factor responsible for the control of cell survival and death to prevent from tumour formation. In vitro and animal studies have indicated that TP53 also responds to metabolic changes and influences metabolic pathways. This study was undertaken to determine the serum level of TP53 and its correlations with clinical and biochemical parameters in type 2 diabetes mellitus (T2DM) patients in comparison to non-diabetic control individuals.

Methods: An observational study was conducted between December 2009 and November 2013 to evaluate TP53 serum level using ELISA. Cases (n=225) were defined as patients who were diagnosed with T2DM. Non-diabetic controls (n=255) were matched by age and sex. Multivariable modelling using logistic regression examined associations between clinical characteristics and TP53 level or T2DM predication was performed.

Results: Serum TP53 level was significantly higher in T2DM patients as compared to non-diabetic healthy controls (1.69 vs 2.07 ng/ml, P<0.001). In T2DM patients, the level of TP53 increased with the age, duration of diabetes and waist-to-hip ratio (WHR) value. A logistic regression analysis revealed that increased serum TP53 level was significantly associated with family history of diabetes, age and WHR. Moreover, TP53, triglyceride and body mass index could be used to predict T2DM.

Interpretation & Conclusions: Our results suggest that TP53 may be linked with T2DM. The fluctuations of serum TP53 level may reflect metabolic and oxidative stress associated with chronic hyperglycaemia. Further studies need to be done to confirm these findings.
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http://dx.doi.org/10.4103/ijmr.IJMR_1401_15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761034PMC
August 2017

Effects of Epothilone A in Combination with the Antidiabetic Drugs Metformin and Sitagliptin in HepG2 Human Hepatocellular Cancer Cells: Role of Transcriptional Factors NF-κB and p53.

Asian Pac J Cancer Prev 2016 ;17(3):993-1001

Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland E-mail :

Type 2 diabetes mellitus patients are at increased risk of many forms of malignancies, especially of the pancreas, colon and hepatocellular cancer. Unfortunately, little is known of the possible interaction between antidiabetic drugs and anticancer agents. The present study investigates the influence of metformin (MET) and sitagliptin (SITA) on the in vitro anticancer activity of the microtubule depolymerization inhibitor agent epothilone A (EpoA). Hepatocellular liver carcinoma cell line (HepG2) viability and apoptosis were determined by the MTT test and by double staining with PO-PRO-1 and 7-aminoactinomycin D, respectively, after treatment with EpoA, metformin or sitagliptin. The levels of nuclear factor NF-κB and p53 were evaluated in the presence and absence of inhibitors. While EpoA and MET inhibited HepG2 cell proliferation, SITA did not. EpoA and SITA induced higher p53 levels than MET. All tested drugs increased the level of NF-κB. Only MET enhanced the proapoptotic effect of EpoA. The EpoA+MET combination evoked the highest cytotoxic effect on HepG2 cells and led to apoptosis independent of p53, decreasing the level of NF-κB. These findings support the link between NF-κB and p53 in the modulation of apoptotic effects in HepG2 cells treated by EpoA. Our studies indicate that the combination of EpoA and MET applied in subtoxic doses has a stronger cytotoxic effect on liver cancer cells than each of the compounds alone. The therapeutic advantages of the combination of EpoA with MET may be valuable in the treatment of patients with diabetes mellitus type 2 (T2DM) and liver cancer.
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http://dx.doi.org/10.7314/apjcp.2016.17.3.993DOI Listing
January 2017

Genetic polymorphisms (Pro197Leu of Gpx1, +35A/C of SOD1, -262C/T of CAT), the level of antioxidant proteins (GPx1, SOD1, CAT) and the risk of distal symmetric polyneuropathy in Polish patients with type 2 diabetes mellitus.

Adv Med Sci 2016 Mar 10;61(1):123-9. Epub 2015 Nov 10.

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Lodz, Poland.

Purpose: Oxidative stress and impaired anti-oxidant defense are regarded as contributory factors for distal symmetric polyneuropathy (DSPN). The purpose of the study was to evaluate the plasma level of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) and the association between polymorphic variants in genes encoding for GPx1, SOD, CAT and the risk of DSPN in T2DM patients.

Material/methods: We included 401 individuals: 110 T2DM patients with DSPN, 135 T2DM patients without DSPN, and 156 control subjects with normoglycemia, and without DSPN. We employed RFPL-PCR to genotype polymorphic variants Pro197Leu of Gpx1, +35A/C of SOD1, -262C/T of CAT and ELISA tests to measure plasma level of SOD1, GPx1 and CAT. The odds ratios (ORs) and 95% confidence intervals (CIs) for each genotype and allele were calculated.

Results: There was a significant decrease in the level of GPx1 (p<0.05), SOD1 (p<0.05) in T2DM patients with DSPN compared to healthy subjects. T2DM patients without DSPN showed a statistically lower serum level of GPX1 (p<0.05) than healthy subjects. SOD 1 and CAT levels were lower in T2DM patients with DSPN compared to T2DM patients without DSPN (p<0.05). The genetic analysis revealed the lack of association between examined polymorphic variants and the risk of DSPN.

Conclusions: The examined polymorphic variants are not associated with DSPN in Polish T2DM patients. The obtained results suggest that disturbances in antioxidant defense system may play significant role in the development and progression of DSPN.
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http://dx.doi.org/10.1016/j.advms.2015.10.006DOI Listing
March 2016

Metformin, but not sitagliptin, enhances WP 631-induced apoptotic HepG2 cell death.

Toxicol In Vitro 2015 Aug 8;29(5):1116-23. Epub 2015 May 8.

Department of Internal Disease, Diabetology and Clinical Pharmacology, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland.

Metformin and sitagliptin are hypoglycemic drugs with potential use in cancer treatment. Evidence indicates that metformin may inhibit the proliferation and growth of various types of cancer cells. Data regarding the relationship between sitagliptin and cancer cells is limited. Therapy based on anthracycline derivatives, mainly doxorubicin, is commonly used in the treatment of resistant liver cancers. WP 631 is a new structural analogue of doxorubicin that exerts an anticancer action by the induction of apoptosis. The aim of this study was to compare the effect of metformin and sitagliptin on WP 631-induced apoptotic cell death in a human hepatocarcinoma cell line (HepG2). HepG2 cancer cells are known to be resistant to chemotherapeutic cytotoxic agents. Both MTT assay and flow cytometry analysis showed that WP 631 reduced the growth of HepG2 cells by apoptosis induction, accompanied by elevated NF-κB and p53 levels. Metformin enhanced the pro-apoptotic effect of WP 631, increasing the NF-κB level but not the p53 level. Sitagliptin did not affect the action of WP 631 in HepG2 cancer cells, however, it increased the p53 level. To conclude, our results suggest that metformin significantly enhances the efficacy of anthracycline derivative, although this effect is not observed in the case of sitagliptin. Therefore, metformin seems to be a good candidate for combined therapy of resistant liver cancer with anthracycline derivatives.
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http://dx.doi.org/10.1016/j.tiv.2015.04.019DOI Listing
August 2015

Analysis of oxidative DNA damage and its repair in Polish patients with diabetes mellitus type 2: Role in pathogenesis of diabetic neuropathy.

Adv Med Sci 2015 Sep 13;60(2):220-30. Epub 2015 Apr 13.

Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, Lodz, Poland.

Purpose: Distal symmetric polyneuropathy (DSPN) is common complication of type 2 diabetes (T2DM). In this work we investigated the role of oxidative damage in connection with particular polymorphisms of DNA repair genes and their repair capacity.

Material/methods: Materials constitute the peripheral blood of patients with T2DM with and without DSPN and control subjects without disturbance of the carbohydrate fraction. The study of gene polymorphisms which products take part in base excision repair (BER) pathway: 726 Val/Ala adenosine diphosphate ribosyl transferase (ADPRT), 324 His/Glu MutYhomolog (MUTYH) and 148 Asp/Glu human apurinic/apyrimidinic endonuclease (APE) was carried out using restriction fragment length polymorphism polymerase chain reaction (PCR-RFLP) method. The study of DNA damage induced by hydrogen peroxide and the efficiency of their repair was carried out using comet assay.

Results: None of the 3 polymorphisms were associated with the risk of DSPN. However, in group of patients together with T2DM and T2DM/DSPN 726 Ala ADPRT allele was significantly susceptible to increased risk of T2DM (OR=1.59; 95% CI: 1.08-2.36). Investigation of DNA damage and repair revealed that T2DM patients have decreased ability to DNA repair. This capacity even drops down in the group of T2DM/DSPN patients compared to subjects with diabetes alone. ADPRT and APE polymorphisms were significantly associated with higher DNA damages (P<0.05) in heterozygous and mutant homozygous in correlation to homozygous wild type, but for MUTYH polymorphism relation was not confirmed.

Conclusions: Pathogenesis of T2DM and development of DSPN may be related to oxidative stress connected with BER gene polymorphisms.
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http://dx.doi.org/10.1016/j.advms.2015.04.001DOI Listing
September 2015

Metformin in cancer prevention and therapy.

Ann Transl Med 2014 Jun;2(6):57

Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Lodz, ul. Pomorska 251, 92-213 Lodz, Poland.

The prevalence of diabetes is dramatically increasing worldwide. The results of numerous epidemiological studies indicate that diabetic population is not only at increased risk of cardiovascular complications, but also at substantially higher risk of many forms of malignancies. The use of metformin, the most commonly prescribed drug for type 2 diabetes, was repeatedly associated with the decreased risk of the occurrence of various types of cancers, especially of pancreas and colon and hepatocellular carcinoma. This observation was also confirmed by the results of numerous meta-analyses. There are however, several unanswered questions regarding the exact mechanism of the anticancer effect of metformin as well as its activity against various types of cancer both in diabetic and nondiabetic populations. In the present work we discuss the proposed mechanism(s) of anticancer effect of metformin and preclinical and clinical data suggesting its anticancer effect in different populations.
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http://dx.doi.org/10.3978/j.issn.2305-5839.2014.06.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200668PMC
June 2014

A case of autoimmune urticaria accompanying autoimmune polyglandular syndrome type III associated with Hashimoto's disease, type 1 diabetes mellitus, and vitiligo.

Endokrynol Pol 2014 ;65(4):320-3

We present a case of autoimmune polyglandular syndrome type III (APS III) associated with Hashimoto's disease, type 1 diabetes mellitus, vitiligo and autoimmune urticaria. This rare genetic disorder occurs with unknown frequency in the Polish population. It is characterised by endocrine tissue destruction resulting in the malfunction of multiple organs.Several cases of APS III associated with organ-specific autoimmune diseases such as coeliac disease, hypogonadism and myasthenia gravis, as well as organ-nonspecific or systemic autoimmune diseases such as sarcoidosis, Sjögren syndrome, and rheumatoid arthritis have been described. To the best of our knowledge, we here describe the first case of APS III associated with autoimmune thyroiditis, type 1 diabetes mellitus, vitiligo and autoimmune urticaria in an adult patient.
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http://dx.doi.org/10.5603/EP.2014.0044DOI Listing
October 2016

Heart failure in the diabetic population - pathophysiology, diagnosis and management.

Arch Med Sci 2014 Jun 27;10(3):546-56. Epub 2014 Jun 27.

Department of Internal Disease, Diabetology and Clinical Pharmacology, Medical University of Lodz, Poland.

Evidence from clinical trials repeatedly confirms the association of diabetes with heart failure, independent of hypertension, atherosclerosis, coronary artery disease and valvular heart disease. However, the importance of coexistence of diabetes and heart failure is not universally recognized, despite the fact that it may significantly contribute to morbidity and mortality of the diabetic population. It seems that prevention of heart failure, early diagnosis, and appropriate management could improve the outcome. Unfortunately, the etiology of heart failure in diabetic patients is still to be elucidated. It is multifactorial in nature and several cellular, molecular and metabolic factors are implicated. Additionally, there are still no definite guidelines on either the diagnosis and treatment of heart failure in diabetic patients or on the therapy of diabetes in subjects with heart failure. This review focuses on the pathophysiology, diagnosis, and prevention of heart failure in the diabetic population as well as management of both comorbidities.
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http://dx.doi.org/10.5114/aoms.2014.43748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107260PMC
June 2014

Advances in the diagnosis and management of diabetic distal symmetric polyneuropathy.

Authors:
Jacek Kasznicki

Arch Med Sci 2014 May 13;10(2):345-54. Epub 2014 May 13.

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Poland.

Distal symmetric polyneuropathy (DSPN) is the most common chronic complication of diabetes mellitus. The pathogenesis of DSPN is not fully elucidated, but it is certainly multifactorial in nature and attributable to metabolic and microvessel disorders related to chronic hyperglycemia, diabetes duration, and several cardiovascular risk factors. Early diagnosis and appropriate management are extremely important, since up to 50% of DSPN cases may be asymptomatic, and patients are unaware of foot injury leading to foot ulcers and amputation. Simple, validated tests such as the Neuropathy Disability Score and/or Vibration Perception Threshold may be used to diagnose DSPN. Similarly, neurological dysfunction screening questionnaires should be used to assess the quality and severity of DSPN symptoms. Using both methods enables prediction of the prognosis of diabetic patients with DSPN. No causative treatment of DSPN is known, but the results of clinical trials indicate that several treatment options are highly effective in symptomatic treatment of painful DSPN. The appropriate treatment of DSPN may improve the outcome, preventing or delaying the development of numerous diabetic complications.
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http://dx.doi.org/10.5114/aoms.2014.42588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4042056PMC
May 2014

Aspirin dose increase from 75 to 150 mg suppresses red blood cell contribution to suboptimal platelet response to aspirin in patients with CAD.

Cardiovasc Drugs Ther 2013 Dec;27(6):549-58

Department of Haemostasis and Haemostatic Disorders, Medical University of Lodz, 113 Zeromski Street, 90-549, Lodz, Poland.

Purpose: To verify the hypothesis that erythrocytes play a role in suboptimal blood platelet response to acetylsalicylic acid (ASA, aspirin) in subjects with coronary artery disease (CAD).

Methods: In a cross-over randomized controlled intervention study we evaluated blood platelet response to 30-day treatment with 75 mg/d or 150 mg/d of ASA (enteric coated) in CAD patients (n = 125). In vitro platelet response to collagen or arachidonic acid was monitored with impedance aggregometry and plasma thromboxane B2 was assayed immunoenzymatically. Blood morphology and several plasma biochemical parameters were determined using routine diagnostic procedures.

Results: CAD patients demonstrated lower blood platelet responsiveness to 75 mg/d of ASA compared to healthy subjects. The improved platelet responsiveness to 150 mg/d of ASA was particularly evident in "poor" responding patients. Positive correlations between platelet "poor" response to lower (75 mg/d) ASA dose and red blood cell count (Rs = 0.215; p < 0.04), haemoglobin (Rs = 0.232; p < 0.02) and haematocrit (Rs = 0.239; p < 0.02) were found in CAD patients. Association between "poor" platelet response with lower ASA dose was confirmed by conditional maximum likelihood logistic regression, which showed the independency between erythrocyte-derived parameters, as the risk factors for suboptimal platelet response to ASA, and other risk factors, like CRP or LDL-cholesterol. In "poor" ASA responders taking the higher ASA dose (150 mg/d) the correlation between platelets' response to ASA and erythrocyte-derived parameters was not significant.

Conclusions: Red blood cell parameters are associated with suboptimal blood platelet response to ASA in patients with CAD. Such a platelet refractoriness to ASA may be effectively overcome by increasing the ASA dose.
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http://dx.doi.org/10.1007/s10557-013-6480-yDOI Listing
December 2013

Relationship between ultrasound features of nonalcoholic fatty liver disease and cardiometabolic risk factors in patients with newly diagnosed type 2 diabetes.

Pol Arch Med Wewn 2013 24;123(9):436-42. Epub 2013 Jun 24.

Introduction:  It is suggested that nonalcoholic fatty liver disease (NAFLD) correlates with cardiometabolic risk factors in patients with newly diagnosed type 2 diabetes.

Objectives:  The aim of this study was to evaluate the prevalence of ultrasound features of NAFLD in patients with newly diagnosed type 2 diabetes and their relationship with cardiometabolic risk factors.

Patients And Methods:  The study included 100 consecutive patients (mean age, 55.64 ±13.42 years) with newly diagnosed type 2 diabetes, without other causes of hepatosteatosis. In each patient, medical history was taken, physical and abdominal ultrasound examinations were performed, and anthropometric and biochemical parameters were measured. Based on the results of an ultrasound examination, patients were assigned to 2 groups: with (n = 71) and without (n = 29) NAFLD.

Results:  NAFLD was present in more than 70% of the patients with diabetes. In patients with NAFLD, significantly higher mean values of body weight, waist and hip circumferences, body mass index, liver enzyme activity, serum C‑reactive protein, total cholesterol, and triglycerides and significantly lower levels of high‑density lipoprotein (HDL) cholesterol were observed. There were no significant differences in the parameters of glycemic control between the groups. A correlation was observed between ultrasound features of NAFLD and some cardiovascular risk factors. Increased waist circumference and serum γ‑glutamyltransferase level and decreased HDL‑cholesterol levels were shown to be independent risk factors of NAFLD.

Conclusions:  Liver ultrasound should be performed in every patient with newly diagnosed type 2 diabetes. Our findings indicate a relationship between NAFLD and multiple cardiometabolic risk factors. The measurement of selected biochemical and anthropometric parameters may be used to assess the risk of NAFLD in this patient group.
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October 2015

Evaluation of oxidative stress markers in pathogenesis of diabetic neuropathy.

Mol Biol Rep 2012 Sep 21;39(9):8669-78. Epub 2012 Jun 21.

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, ul. Parzeczewska 35, 95-100 Zgierz, Poland.

Experimental evidences suggest that hyperglycaemia-induced overproduction of reactive oxygen species and subsequent damage to proteins, lipids and DNA may play a key role in the development of distal symmetric polyneuropathy (DSPN)-the most common complication of diabetes mellitus. The study population consisted of 51 individuals aged 52-82 years classified into 3 groups: 16 patients diagnosed with type 2 diabetes mellitus (T2DM) with DSPN, 16 T2DM patients without DSPN and 19 control subjects without diabetes and neuropathy. The study was conducted to determine the activity of antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPX) and total antioxidant status (TAS) in the examined groups. An alkaline comet assay was used to determine the extent of DNA damage of oxidized purines as glicosylo-formamidoglicosylase (Fpg) sites, and oxidized pyrimidines as endonuclease III (Nth) sites. A significant decrease of SOD (P < 0.05), GPX (P < 0.05) and nonsignificant decrease of CAT (P > 0.05), and TAS status (P > 0.05) were seen in T2DM patients with neuropathy compared to T2DM patients as well as controls. T2DM patients with or without neuropathy revealed significantly lower (P < 0.05) plasma concentration of nitrous oxide compared to the control subjects. Endogenous level of oxidative DNA damage in T2DM patients with DSPN was significantly higher compared both to the controls and T2DM patients without DSPN (P < 0.001). Moreover, lymphocytes isolated from T2DM patients with DSPN were more susceptible to oxidative DNA lesions induced by hydrogen peroxide than from T2DM patients without DSPN (P < 0.001). Our results confirm hypothesis that oxidative stress may play a substantial role in the development and progression of diabetic distal symmetric polyneuropathy.
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http://dx.doi.org/10.1007/s11033-012-1722-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404273PMC
September 2012

Gliclazide may have an antiapoptotic effect related to its antioxidant properties in human normal and cancer cells.

Mol Biol Rep 2012 May 20;39(5):5253-67. Epub 2011 Dec 20.

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Parzeczewska 35, Zgierz, 95-100, Lodz, Poland.

Experimental and clinical studies suggest that gliclazide may protect pancreatic β-cells from apoptosis induced by an oxidative stress. However, the precise mechanism(s) of this action are not fully understood and requires further clarification. Therefore, using human normal and cancer cells we examined whether the anti-apoptotic effects of this sulfonylurea is due to its free radical scavenger properties. Hydrogen peroxide (H(2)O(2)) as a model trigger of oxidative stress was used to induce cell death. Our experiments were performed on human normal cell line (human umbilical vein endothelial cell line, HUVEC-c) and human cancer cell lines (human mammary gland cell line, Hs578T; human pancreatic duct epithelioid carcinoma cell line, PANC-1). To assess the effect of gliclazide the cells were pre-treated with the drug. The 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay was employed to measure the impact of gliclazide on cell viability. Generation of reactive oxygen species, mitochondrial membrane potential (∆Ψ(m)), and intracellular Ca(2+) concentration [Ca(2+)] were monitored. Furthermore, the morphological changes associated with apoptosis were determined using double staining with Hoechst 33258-propidium iodide (PI). Gliclazide protects the tested cells from H(2)O(2)-induced cell death most likely throughout the inhibition of ROS production. Moreover, the drug restored loss of ΔΨ(m) and diminished intracellular [Ca(2+)] evoked by H(2)O(2). Double staining with Hoechst 33258-PI revealed that pre-treatment with gliclazide diminished the number of apoptotic cells. Our findings indicate that gliclazide may protect both normal and cancer human cells against apoptosis induced by H(2)O(2). It appears that the anti-apoptotic effect of the drug is most likely associated with reduction of oxidative stress.
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http://dx.doi.org/10.1007/s11033-011-1323-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310990PMC
May 2012

Perspectives on the use of melatonin to reduce cytotoxic and genotoxic effects of methacrylate-based dental materials.

J Pineal Res 2011 Sep 7;51(2):157-62. Epub 2011 Apr 7.

Department of Molecular Genetics, University of Lodz, Lodz, Poland.

Melatonin (5-methoxy-N-acetyltryptamine), an indoleamine produced in the pineal gland and many other organs, displays a wide spectrum of protective effects against cell injury of various origins. Contemporary dental restorative materials mainly consist of methacrylate polymers with some additives. However, because of the incompleteness of polymerization process in situ as well as mechanical shearing and enzymatic degradation, methacrylate monomers are released from the restoration into the oral cavity and the pulp, from where they gain access to other tissues and organs. Such monomers have displayed toxic properties in many in vivo and in vitro studies, including cytotoxicity and genotoxicity and a considerable portion of these effects is underlined by the oxidative action of these compounds. As melatonin shows biocompatibility with the oral cavity and displays antioxidative properties, it may be considered as a protective agent against harmful effects of methacrylate monomers derived from dental restorations. Melatonin decreases cytotoxic and genotoxic effects of methacrylate monomers used in dentistry, and it does not influence the bond strength of dental composites. This opens a new possible application of melatonin to improve properties of biomaterials used in dentistry.
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http://dx.doi.org/10.1111/j.1600-079X.2011.00877.xDOI Listing
September 2011

Cytotoxicity and genotoxicity of capecitabine in head and neck cancer and normal cells.

Mol Biol Rep 2011 Aug 24;38(6):3679-88. Epub 2010 Nov 24.

Department of Gastroenterology and Internal Medicine, Medical University of Lodz, 90-647, Lodz, Poland.

The interaction between a chemical and a cell may strongly depend on whether this cell is normal or pathological. Side effects of anticancer drugs may sometimes overcome their benefit action, so it is important to investigate their effect in both the target and normal cells. Capecitabine (Xeloda, CAP), a prodrug of 5-fluorouracil, is mainly used in colon cancer, but little is known about its action in head and neck cancer. We compared the cyto- and genotoxicity of CAP in head and neck HTB-43 cells and normal human lymphocytes by comet assay and flow cytometry. CAP at concentration up to 50 μM significantly decreased the viability of the cancer cells, whereas it did not affect normal lymphocytes. The drug did not interact with isolated plasmid DNA, but it damaged DNA in both cancer and normal cells. However, the extent of the damage in the former was much higher than in the latter. CAP induced apoptosis in the cancer cells, but not in normal lymphocytes. Pre-treatment of the cells with the nitrone spin traps α-(4-pyridil-1-oxide)-N-tert-butylnitrone and N-tert-butyl-α-phenylnitrone decreased the extent of CAP induced DNA damage, suggesting that free radicals may be involved in the formation of DNA lesions induced by CAP. The drug evoked an increase in the G0/G1 cell population accompanied by a decrease in the S cell population. CAP may evoke a pronounced cyto- and genotoxic effects in head and neck cancer cells, whereas it may or may not induce such effects in normal cells to far lesser extent.
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http://dx.doi.org/10.1007/s11033-010-0482-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3115142PMC
August 2011

The role of "metabolic memory" in the natural history of diabetes mellitus.

Pol Arch Med Wewn 2009 Jul-Aug;119(7-8):493-500

Department of Internal Diseases, Diabetology and Clinical Pharmacology, Medical University of Łodź, Zgierz, Poland.

There is growing evidence that early, intensive treatment of new-onset diabetes mellitus aimed at tight glucose control reduces the risk of micro- and macrovascular complications. Metabolic memory is a term used to describe beneficial effects of immediate intensive treatment of hyperglycemia and the observation that they are maintained for many years, regardless of glycemia in the later course of diabetes. This phenomenon was first observed in preclinical studies and was later confirmed in large clinical trials. It has been suggested that early glycemia normalization can halt hyperglycemia-induced pathological processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids. The phenomenon of metabolic memory suggests that antioxidants and agents degrading advanced glycation end products in addition to strict hypoglycemic treatment can be used to prevent chronic diabetic complications.
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October 2009

Association between polymorphisms of the DNA repair genes XRCC1 and hOGG1 and type 2 diabetes mellitus in the Polish population.

Pol Arch Med Wewn 2009 Mar;119(3):122-8

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Łódź, Zgierz, Poland.

Introduction: Elevated oxidative stress in type 2 diabetic patients leads to the accumulation of DNA damage and possibly acceleration of diabetic complications. Numerous studies indicate that diabetic patients may display impaired DNA repair compared to healthy subjects.

Objectives: The aim of the study was to compare the distribution of genotypes of DNA repair genes between type 2 diabetic patients and non-diabetic subjects.

Patients And Methods: Polymerase chain reaction-based restriction fragment length polymorphism was used to determine the distribution of genotypes and frequency of alleles of polymorphisms of base excision repair genes, including the Arg399Gln polymorphism of the XRCC1 gene and Ser326Cys in the hOGG1 gene. The study population included 195 subjects, including 94 with type 2 diabetes mellitus and 101 with normal glucose metabolism. All study participants were Caucasian and inhabited the city of Łódź, Poland.

Results: The frequency of the Gln allele in XRCC1 gene (41% vs. 47%, odds ratio [OR] 0.80, CI 0.54-1.19) and Cys allele in hOGG1 gene (19% vs. 18%, OR 1.09, CI 0.65-1.82) did not differ significantly between diabetic patients and subjects with normal glucose metabolism. Linkage analysis revealed that the Arg/Gln-Ser/Ser combination of genotypes of XRCC1 and hOGG1, respectively (not associated with a decreased activity of both genes) occurs more commonly in type 2 diabetic patients.

Conclusions: The results of our study suggest no association between decreased activity of the examined DNA repair genes and type 2 diabetes mellitus in the studied population.
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March 2009

Gene polymorphisms and antigen levels of matrix metalloproteinase-1 in type 2 diabetes mellitus coexisting with coronary heart disease.

Kardiol Pol 2008 Oct;66(10):1042-8; discussion 1049

Medical University, Łódź, Poland.

Background And Aim: Diabetes mellitus is a major risk factor for coronary heart disease (CHD). Matrix metalloproteinases (MMPs) can play a pivotal role in the remodelling of extracellular matrix associated with the development of atherosclerosis. Therefore, the aim of the study was to compare the distribution of genotypes and frequency of alleles of two polymorphisms of the MMP-1 gene promoter, an A/G substitution and a 1G/2G insertion, in correlation with antigen levels of matrix metalloproteinase-1 (MMP-1) in type 2 diabetic patients with or without CHD as well as individuals with normal glucose level without CHD.

Methods: Genotypes of 115 patients with type 2 diabetes mellitus (T2DM) and a subpopulation of 66 patients with coexisting CHD as well as 120 non-diabetic control subjects were determined by PCR-based restriction fragment length polymorphism (PCR-RFLP).

Results: We demonstrated that antigen levels of MMP-1 in the serum of diabetic patients were significantly higher than those of individuals with normal glucose metabolism (p <0.05). Elevated levels of MMP-1 positively correlated with CHD occurrence in T2DM patients (p <0.01). The distribution of genotypes revealed higher frequency of the 2G/2G polymorphism variant in diabetic patients with CHD [OR 5.76, 95% CI (1.24; 26.87)], thus suggesting its strong association with high level of MMP-1. In T2DM patients with coexisting CHD, a higher frequency of the 2G allele of 1G/2G [OR 1.74, CI 95% (1.01; 2.99)] and the G allele of A/G polymorphism [OR 2.15, 95% CI (1.22; 3.80)] was also found.

Conclusion: Our results suggest that type 2 diabetes mellitus is linked with elevated blood level of MMP-1, and polymorphisms of the promoter region of its gene might be associated with CHD.
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October 2008

In vitro effect of gliclazide on DNA damage and repair in patients with type 2 diabetes mellitus (T2DM).

Chem Biol Interact 2008 Jun 8;173(3):159-65. Epub 2008 Apr 8.

Department of Internal Medicine, Diabetology and Clinical Pharmacology, Medical University of Lodz, Zgierz, Poland.

Type 2 diabetes mellitus is associated with elevated level of oxidative stress, which is one of the most important factors responsible for the development of chronic complications of this disease. Moreover, it was shown that diabetic patients had increased level of oxidative DNA damage and decreased effectiveness of DNA repair. These changes may be associated with increased risk of cancer in T2DM patients, since DNA damage and DNA repair play a pivotal role in malignant transformation. It was found that gliclazide, an oral hypoglycemic drug with antioxidant properties, diminished DNA damage induced by free radicals. Therefore, the aim of the present study was to evaluate the in vitro impact of gliclazide on: (i) endogenous basal and oxidative DNA damage, (ii) DNA damage induced by hydrogen peroxide and (iii) the efficacy of DNA repair of such damage. DNA damage and DNA repair in peripheral blood lymphocytes of 30 T2DM patients and 30 non-diabetic individuals were evaluated by alkaline single cell electrophoresis (comet) assay. The extent of oxidative DNA damage was assessed by DNA repair enzymes: endonuclease III and formamidopyrimidine-DNA glycosylase. The endogenous basal and oxidative DNA damages were higher in lymphocytes of T2DM patients compared to non-diabetic subjects and gliclazide decreased the level of such damage. The drug significantly decreased the level of DNA damage induced by hydrogen peroxide in both groups. Gliclazide increased the effectiveness of DNA repair in lymphocytes of T2DM patients (93.4% (with gliclazide) vs 79.9% (without gliclazide); P< or =0.001) and non-diabetic subjects (95.1% (with gliclazide) vs 90.5% (without gliclazide); P< or =0.001). These results suggest that gliclazide may protect against the oxidative stress-related chronic diabetes complications, including cancer, by decreasing the level of DNA damage induced by reactive oxygen species.
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http://dx.doi.org/10.1016/j.cbi.2008.03.017DOI Listing
June 2008

DNA damage and repair in type 2 diabetes mellitus.

Mutat Res 2004 Oct;554(1-2):297-304

Department of Molecular Genetics, University of Lodz, Banacha 12/16, 90-237, Poland.

DNA damage may be associated with type 2 diabetes mellitus (T2DM) and its complications mainly through oxidative stress. Little is known about DNA repair disturbances potentially contributing to the overall extent of DNA damage in T2DM, which, in turn, may be linked with genomic instability resulting in cancer. To assess whether DNA repair may be perturbed in 2DM we determined: (1) the level of endogenous basal DNA damage, this means damage recognized in the alkaline comet assay (DNA strand breaks and alkali labile sites) as well as endogenous oxidative and alkylative DNA damage (2) the sensitivity to DNA-damaging agents hydrogen peroxide and doxorubicin and the efficacy of removing of DNA damage induced by these agents in peripheral blood lymphocytes of T2DM patients and healthy individuals. The level of DNA damage and the kinetics of DNA repair was evaluated by the alkaline single cell gel electrophoresis (comet assay). Oxidative and alkylative DNA damage were assayed with the use of DNA repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg), recognizing oxidized DNA bases and 3-methyladenine-DNA glycosylase II (AlkA) recognizing alkylated bases. The levels of basal endogenous and oxidative DNA damage in diabetes patients were higher than in control subjects. There was no difference between the level of alkylative DNA in the patients and the controls. Diabetes patients displayed higher susceptibility to hydrogen peroxide and doxorubicin and decreased efficacy of repairing DNA damage induced by these agents than healthy controls. Our results suggest that type 2 diabetes mellitus may be associated not only with the elevated level of oxidative DNA damage but also with the increased susceptibility to mutagens and the decreased efficacy of DNA repair. These features may contribute to a link between diabetes and cancer and metrics of DNA damage and repair, measured by the comet assay, may be markers of risk of cancer in diabetes.
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http://dx.doi.org/10.1016/j.mrfmmm.2004.05.011DOI Listing
October 2004