Partner: Agnieszka Śliwińska

Medical University of Lodz (PL)

Recent publications
1.Czarny P., Kwiatkowski D., Toma M., Kubiak J., Sliwinska A., Talarowska M., Szemraj J., Maes M., Galecki P., Sliwinski T., Impact of single-nucleotide polymorphisms of base excision repair genes on DNA damage and efficiency of DNA repair in recurrent depression disorder, MOLECULAR NEUROBIOLOGY, ISSN: 0893-7648, DOI: 10.1007/s12035-016-9971-6, Vol.54, No.6, pp.4150-4159, 2017
Abstract:

Elevated level of DNA damage was observed in patients with depression. Furthermore, single nucleotide polymorphisms (SNPs) of base excision repair (BER) genes may modulate the risk of this disease. Therefore, the aim of this study was to delineate the association between DNA damage, DNA repair, the presence of polymorphic variants of BER genes, and occurrence of depression. The study was conducted on peripheral blood mononuclear cells of 43 patients diagnosed with depression and 59 controls without mental disorders. Comet assay was used to assess endogenous (oxidative) DNA damage and efficiency of DNA damage repair (DRE). TaqMan probes were employed to genotype 12 SNPs of BER genes. Endogenous DNA damage was higher in the patients than in the controls, but none of the SNPs affected its levels. DRE was significantly higher in the controls and was modulated by BER SNPs, particularly by c.977C > G-hOGG1, c.972G > C-MUTYH, c.2285T > C-PARP1, c.580C > T-XRCC1, c.1196A > G-XRCC1, c.444T > G-APEX1, c.-468T > G-APEX1, or c.*50C > T-LIG3. Our study suggests that both oxidative stress and disorders in DNA damage repair mechanisms contribute to elevated levels of DNA lesions observed in depression. Lower DRE can be partly attributed to the presence of specific SNP variants.

Keywords:

Recurrent depression disorder, DNA damage, DNA repair, Oxidative stress, Base excision repair, Single nucleotide polymorphism

Affiliations:
Czarny P.-Medical University of Lodz (PL)
Kwiatkowski D.-other affiliation
Toma M.-University of Lodz (PL)
Kubiak J.-University of Lodz (PL)
Sliwinska A.-Medical University of Lodz (PL)
Talarowska M.-Medical University of Lodz (PL)
Szemraj J.-Medical University of Lodz (PL)
Maes M.-Deakin University (AU)
Galecki P.-Medical University of Lodz (PL)
Sliwinski T.-University of Lodz (PL)
2.Sliwinska A., Sitarek P., Toma M., Czarny P., Synowiec E., Krupa R., Wigner P., Bialek K., Kwiatkowski D., Korycinska A., Majsterek I., Szemraj J., Galecki P., Sliwinski T., Decreased expression level of BER genes in Alzheimer's disease patients is not derivative of their DNA methylation status, PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY, ISSN: 0278-5846, DOI: 10.1016/j.pnpbp.2017.07.010, Vol.79, pp.311-316, 2017
Abstract:

Background: Neurodegeneration in Alzheimer's disease can be caused by accumulation of oxidative DNA damage resulting from altered expression of genes involved in the base excision repair system (BER). Promoter methylation can affect the profile of BER genes expression. Decreased expression of BER genes was observed in the brains of AD patients.
Aim of the study: The aim of our study was to compare the expression and methylation profiles of six genes coding for proteins involved in BER, namely: hOGG1, APE1, MUTYH, NEIL1, PARP1 and XRCC1, in the peripheral blood cells of AD patients and healthy volunteers.
Methods: The study consisted of 100 persons diagnosed with Alzheimer's disease according to DSM-IV criteria, and 110 healthy volunteers. DNA and total RNA were isolated from venous blood cells. Promoter methylation profiles were obtained by High Resolution Melting (HRM) analysis of bisulfide converted DNA samples. Real-time PCR with TaqMan probes was employed for gene expression analysis.
Results: APE1, hOGG1, MUTYH, PARP1 and NEIL1 were significantly (p < 0.001) down-regulated in the lymphocytes of AD patients, as compared to healthy volunteers. Expression of XRCC1 didn't differ significantly between both groups. We did not find any differences in the methylation pattern of any of the investigated BER genes.
Conclusions: The methylation status of promoters is not associated with downregulation of BER genes. Our results show that downregulation of BER genes detected in peripheral blood samples could reflect the changes occurring in the brain of patients with AD, and may be a useful biomarker of this disease.

Keywords:

Alzheimer's disease, DNA base excision repair genes, Gene expression, Promoter methylation

Affiliations:
Sliwinska A.-Medical University of Lodz (PL)
Sitarek P.-Medical University of Lodz (PL)
Toma M.-University of Lodz (PL)
Czarny P.-Medical University of Lodz (PL)
Synowiec E.-University of Lodz (PL)
Krupa R.-University of Lodz (PL)
Wigner P.-University of Lodz (PL)
Bialek K.-University of Lodz (PL)
Kwiatkowski D.-other affiliation
Korycinska A.-University of Lodz (PL)
Majsterek I.-Medical University of Lodz (PL)
Szemraj J.-Medical University of Lodz (PL)
Galecki P.-Medical University of Lodz (PL)
Sliwinski T.-University of Lodz (PL)
3.Kwiatkowski D., Czarny P., Toma M., Jurkowska N., Śliwinska A., Drzewoski J., Bachurska A., Szemraj J., Maes M., Berk M., Su K.P., Gałecki P., Śliwiński T., Associations between DNA Damage, DNA Base Excision Repair Gene Variability and Alzheimer's Disease Risk, DEMENTIA AND GERIATRIC COGNITIVE DISORDERS, ISSN: 1420-8008, DOI: 10.1159/000443953, Vol.41, No.3-4, pp.152-171, 2016
Abstract:

Background: Increased oxidative damage to DNA is one of the pathways involved in Alzheimer's disease (AD). Insufficient base excision repair (BER) is in part responsible for increased oxidative DNA damage. The aim of the present study was to assess the effect of polymorphic variants of BER-involved genes and the peripheral markers of DNA damage and repair in patients with AD. Material and Methods: Comet assays and TaqMan probes were used to assess DNA damage, BER efficiency and polymorphic variants of 12 BER genes in blood samples from 105 AD patients and 130 controls. The DNA repair efficacy (DRE) was calculated according to a specific equation. Results: The levels of endogenous and oxidative DNA damages were higher in AD patients than controls. The polymorphic variants of XRCC1 c.580C>T XRCC1 c.1196A>G and OGG1 c.977C>G are associated with increased DNA damage in AD. Conclusion: Our results show that oxidative stress and disturbances in DRE are particularly responsible for the elevated DNA lesions in AD. The results suggest that oxidative stress and disruption in DNA repair may contribute to increased DNA damage in AD patients and risk of this disease. In addition, disturbances in DRE may be associated with polymorphisms of OGG1 and XRCC1.

Keywords:

DNA damage, DNA base excision repair, Alzheimer's disease risk, Dementia, Oxidative stress

Affiliations:
Kwiatkowski D.-other affiliation
Czarny P.-Medical University of Lodz (PL)
Toma M.-University of Lodz (PL)
Jurkowska N.-University of Lodz (PL)
Śliwinska A.-Medical University of Lodz (PL)
Drzewoski J.-Medical University of Lodz (PL)
Bachurska A.-Medical University of Lodz (PL)
Szemraj J.-Medical University of Lodz (PL)
Maes M.-Deakin University (AU)
Berk M.-Deakin University (AU)
Su K.P.-China Medical University Hospital (TW)
Gałecki P.-Medical University of Lodz (PL)
Śliwiński T.-University of Lodz (PL)
4.Sliwinska A., Kwiatkowski D., Czarny P., Toma M., Wigner P., Drzewoski J., Fabianowska-Majewska K., Szemraj J., Maes M., Gałecki P., Śliwiński T., The levels of 7,8-dihydrodeoxyguanosine (8-oxoG) and 8-oxoguanine DNA glycosylase 1 (OGG1) - A potential diagnostic biomarkers of Alzheimer's disease, JOURNAL OF THE NEUROLOGICAL SCIENCES, ISSN: 0022-510X, DOI: 10.1016/j.jns.2016.07.008, Vol.368, pp.155-159, 2016
Abstract:

Evidence indicates that oxidative stress contributes to neuronal cell death in Alzheimer's disease (AD). Increased oxidative DNA damage I, as measured with 8-oxoguanine (8-oxoG), and reduced capacity of proteins responsible for removing of DNA damage, including 8-oxoguanine DNA glycosylase 1 (OGG1), were detected in brains of AD patients. In the present study we assessed peripheral blood biomarkers of oxidative DNA damage, i.e. 8-oxoG and OGG1, in AD diagnosis, by comparing their levels between the patients and the controls. Our study was performed on DNA and serum isolated from peripheral blood taken from 100 AD patients and 110 controls. For 8-oxoG ELISA was employed. The OGG1 level was determined using ELISA and Western blot technique. Levels of 8-oxoG were significantly higher in DNA of AD patients. Both ELISA and Western blot showed decreased levels of OGG1 in serum of AD patients. Our results show that oxidative DNA damage biomarkers detected in peripheral tissue could reflect the changes occurring in the brain of patients with AD. These results also suggest that peripheral blood samples may be useful to measure oxidative stress biomarkers in AD.

Keywords:

Alzheimer's disease, Oxidative stress, Oxidative DNA damage, 7 8-dihydrodeoxyguanosine (8-oxoG), DNA base excision repair, 8-oxoguanine DNA glycosylase 1 (OGG1)

Affiliations:
Sliwinska A.-Medical University of Lodz (PL)
Kwiatkowski D.-other affiliation
Czarny P.-Medical University of Lodz (PL)
Toma M.-University of Lodz (PL)
Wigner P.-University of Lodz (PL)
Drzewoski J.-Medical University of Lodz (PL)
Fabianowska-Majewska K.-Medical University of Lodz (PL)
Szemraj J.-Medical University of Lodz (PL)
Maes M.-Deakin University (AU)
Gałecki P.-Medical University of Lodz (PL)
Śliwiński T.-University of Lodz (PL)
5.Śliwińska A., Kwiatkowski D., Czarny P., Milczarek J., Toma M., Korycinska A., Szemraj J., Śliwiński T., Genotoxicity and cytotoxicity of ZnO and Al2O3 nanoparticles, TOXICOLOGY MECHANISMS AND METHODS, ISSN: 1537-6516, DOI: 10.3109/15376516.2015.1006509, Vol.25, No.3, pp.176-183, 2015
Abstract:

Objectives: Metal oxide nanoparticles (ZnO-NPs and Al2O3-NPs) are used in many fields, including consumer products and biomedical applications. As a result, exposure to these NPs is highly frequent, however, no conclusive information on their potential cytotoxicity and genotoxicity mechanisms are available. For this reason, we studied cytotoxic and genotoxic effects of ZnO-NPs and Al2O3-NPs on human peripheral blood lymphocytes.

Materials and methods: We obtained our goals by using MTT assay, Annexin V-FITC flow cytometry, and alkaline, neural and pH 12.1 versions of comet assay.

Results: Exposure of lymphocytes to both NPs for 24 h slightly decreased viability of lymphocytes at >= 0.5 mM. For the first time, we revealed using the comet assays that both ZnO-NPs and Al2O3-NPs caused a concentration-dependent increase of DNA single-strand breaks, but not alkali-labile sites. Treatment with DNA glycosylases showed that the NPs induced oxidative DNA damage. DNA damage caused by both nanoparticles at 0.05 mM was removed within 120 min, however lymphocytes did not repair DNA damage induced by 0.5 mM NPs. Studied nanoparticles did not induce apoptosis in lymphocytes.

Conclusion: Our results suggest that ZnO-NPs and Al2O3-NPs at concentration up to 0.5 mM did not exhibit cytotoxic effect but may exert genotoxic effect on lymphocytes, at least partially by the generation of oxidative DNA damage and strand breaks.

Keywords:

DNA repair, oxidative DNA damage, single and double strand breaks

Affiliations:
Śliwińska A.-Medical University of Lodz (PL)
Kwiatkowski D.-other affiliation
Czarny P.-Medical University of Lodz (PL)
Milczarek J.-University of Lodz (PL)
Toma M.-University of Lodz (PL)
Korycinska A.-University of Lodz (PL)
Szemraj J.-Medical University of Lodz (PL)
Śliwiński T.-University of Lodz (PL)