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Reversible cellular senescence was demonstrated previously to constitute colon cancer cell response to methotrexate. The current study presents a comparison of two senescent states of colon cancer cells, arrested and reversing, resulting from respectively, 120 h exposure to the drug, and 48 h exposure followed by 96 h regrowth in drug-free media. The upregulation of immunoproteasome subunit-coding genes and the increase in human leukocyte antigen HLA-A/B/C membrane level indicated MHC-I-restricted antigen presentation as common to both senescent states. Nuclear factor NF-κB p65 level decreased and activating protein AP-1: c-Jun, Fra2 and JunB nuclear levels increased in both senescent cell populations. Notably, the increase in AP-1- dependent transcription occurred after 48 h exposure to methotrexate. β-catenin nuclear level increased after 48 h exposure to the drug and remained as such only in senescence-arrested cells. β-catenin level was found uncoupled from the protein phosphorylation status indicating the deregulation of β-catenin signaling in colon cancer cells employed in the study. These findings carry implications for both, a general mechanism of senescence establishment and putative advantages for colon cancer treatment.
Magdalena Dabrowska; Lukasz Uram; Michal Dabrowski; Ewa Sikora. Antigen presentation capability and AP-1 activation accompany methotrexate-induced colon cancer cell senescence in the context of aberrant β-catenin signaling. Mechanisms of Ageing and Development 2021, 197, 111517 .
AMA StyleMagdalena Dabrowska, Lukasz Uram, Michal Dabrowski, Ewa Sikora. Antigen presentation capability and AP-1 activation accompany methotrexate-induced colon cancer cell senescence in the context of aberrant β-catenin signaling. Mechanisms of Ageing and Development. 2021; 197 ():111517.
Chicago/Turabian StyleMagdalena Dabrowska; Lukasz Uram; Michal Dabrowski; Ewa Sikora. 2021. "Antigen presentation capability and AP-1 activation accompany methotrexate-induced colon cancer cell senescence in the context of aberrant β-catenin signaling." Mechanisms of Ageing and Development 197, no. : 111517.
The p21WAF1/Cip1 protein, encoded by CDKN1A, plays a vital role in senescence, and its transcriptional control by the tumour suppressor p53 is well-established. However, p21 can also be regulated in a p53-independent manner, by mechanisms that still remain less understood. We aimed to expand the knowledge about p53-independent senescence by looking for novel players involved in CDKN1A regulation. We used a chromatin-directed proteomic approach and identified ZNF84 as a novel regulator of p21 in various p53-deficient cell lines treated with cytostatic dose of doxorubicin. Knock-down of ZNF84, an as-yet un-characterized protein, inhibited p21 gene and protein expression in response to doxorubicin, it attenuated senescence and was associated with enhanced proliferation, indicating that ZNF84-deficiency can favor senescence bypass. ZNF84 deficiency was also associated with transcriptomic changes in genes governing various cancer-relevant processes e.g., mitosis. In cells with ZNF84 knock-down we discovered significantly lower level of H2AX Ser139 phosphorylation (γH2AX), which is triggered by DNA double strand breaks. Intriguingly, we observed a reverse correlation between the level of ZNF84 expression and survival rate of colon cancer patients. In conclusion, ZNF84, whose function was previously not recognized, was identified here as a critical p53-independent regulator of senescence, opening possibilities for its targeting in novel therapies of p53-null cancers.
Anna Strzeszewska-Potyrała; Karolina Staniak; Joanna Czarnecka-Herok; Mahmoud-Reza Rafiee; Marcin Herok; Grażyna Mosieniak; Jeroen Krijgsveld; Ewa Sikora. Chromatin-Directed Proteomics Identifies ZNF84 as a p53-Independent Regulator of p21 in Genotoxic Stress Response. Cancers 2021, 13, 2115 .
AMA StyleAnna Strzeszewska-Potyrała, Karolina Staniak, Joanna Czarnecka-Herok, Mahmoud-Reza Rafiee, Marcin Herok, Grażyna Mosieniak, Jeroen Krijgsveld, Ewa Sikora. Chromatin-Directed Proteomics Identifies ZNF84 as a p53-Independent Regulator of p21 in Genotoxic Stress Response. Cancers. 2021; 13 (9):2115.
Chicago/Turabian StyleAnna Strzeszewska-Potyrała; Karolina Staniak; Joanna Czarnecka-Herok; Mahmoud-Reza Rafiee; Marcin Herok; Grażyna Mosieniak; Jeroen Krijgsveld; Ewa Sikora. 2021. "Chromatin-Directed Proteomics Identifies ZNF84 as a p53-Independent Regulator of p21 in Genotoxic Stress Response." Cancers 13, no. 9: 2115.
Autophagy is an evolutionarily conserved process necessary to maintain cell homeostasis in response to various forms of stress such as nutrient deprivation and hypoxia as well as functioning to remove damaged molecules and organelles. The role of autophagy in cancer varies depending on the stage of cancer. Cancer therapeutics can also simultaneously evoke cancer cell senescence and ploidy increase. Both cancer cell senescence and polyploidization are reversible by depolyploidization giving rise to the progeny. Autophagy activation may be indispensable for cancer cell escape from senescence/polyploidy. As cancer cell polyploidy is proposed to be involved in cancer origin, the role of autophagy in polyploidization/depolyploidization of senescent cancer cells seems to be crucial. Accordingly, this review is an attempt to understand the complicated interrelationships between reversible cell senescence/polyploidy and autophagy.
Magdalena Dudkowska; Karolina Staniak; Agnieszka Bojko; Ewa Sikora. The role of autophagy in escaping therapy-induced polyploidy/senescence. Advances in Cancer Research 2021, 150, 209 -247.
AMA StyleMagdalena Dudkowska, Karolina Staniak, Agnieszka Bojko, Ewa Sikora. The role of autophagy in escaping therapy-induced polyploidy/senescence. Advances in Cancer Research. 2021; 150 ():209-247.
Chicago/Turabian StyleMagdalena Dudkowska; Karolina Staniak; Agnieszka Bojko; Ewa Sikora. 2021. "The role of autophagy in escaping therapy-induced polyploidy/senescence." Advances in Cancer Research 150, no. : 209-247.
Aging of the brain can manifest itself as a memory and cognitive decline, which has been shown to frequently coincide with changes in the structural plasticity of dendritic spines. Decreased number and maturity of spines in aged animals and humans, together with changes in synaptic transmission, may reflect aberrant neuronal plasticity directly associated with impaired brain functions. In extreme, a neurodegenerative disease, which completely devastates the basic functions of the brain, may develop. While cellular senescence in peripheral tissues has recently been linked to aging and a number of aging-related disorders, its involvement in brain aging is just beginning to be explored. However, accumulated evidence suggests that cell senescence may play a role in the aging of the brain, as it has been documented in other organs. Senescent cells stop dividing and shift their activity to strengthen the secretory function, which leads to the acquisition of the so called senescence-associated secretory phenotype (SASP). Senescent cells have also other characteristics, such as altered morphology and proteostasis, decreased propensity to undergo apoptosis, autophagy impairment, accumulation of lipid droplets, increased activity of senescence-associated-β-galactosidase (SA-β-gal), and epigenetic alterations, including DNA methylation, chromatin remodeling, and histone post-translational modifications that, in consequence, result in altered gene expression. Proliferation-competent glial cells can undergo senescence both in vitro and in vivo, and they likely participate in neuroinflammation, which is characteristic for the aging brain. However, apart from proliferation-competent glial cells, the brain consists of post-mitotic neurons. Interestingly, it has emerged recently, that non-proliferating neuronal cells present in the brain or cultivated in vitro can also have some hallmarks, including SASP, typical for senescent cells that ceased to divide. It has been documented that so called senolytics, which by definition, eliminate senescent cells, can improve cognitive ability in mice models. In this review, we ask questions about the role of senescent brain cells in brain plasticity and cognitive functions impairments and how senolytics can improve them. We will discuss whether neuronal plasticity, defined as morphological and functional changes at the level of neurons and dendritic spines, can be the hallmark of neuronal senescence susceptible to the effects of senolytics.
Ewa Sikora; Anna Bielak-Zmijewska; Magdalena Dudkowska; Adam Krzystyniak; Grazyna Mosieniak; Malgorzata Wesierska; Jakub Wlodarczyk. Cellular Senescence in Brain Aging. Frontiers in Aging Neuroscience 2021, 13, 1 .
AMA StyleEwa Sikora, Anna Bielak-Zmijewska, Magdalena Dudkowska, Adam Krzystyniak, Grazyna Mosieniak, Malgorzata Wesierska, Jakub Wlodarczyk. Cellular Senescence in Brain Aging. Frontiers in Aging Neuroscience. 2021; 13 ():1.
Chicago/Turabian StyleEwa Sikora; Anna Bielak-Zmijewska; Magdalena Dudkowska; Adam Krzystyniak; Grazyna Mosieniak; Malgorzata Wesierska; Jakub Wlodarczyk. 2021. "Cellular Senescence in Brain Aging." Frontiers in Aging Neuroscience 13, no. : 1.
NADPH oxidases (NOX) are commonly expressed ROS-producing enzymes that participate in the regulation of many signaling pathways, which influence cell metabolism, survival, and proliferation. Due to their high expression in several different types of cancer it was postulated that NOX promote tumor progression, growth, and survival. Thus, the inhibition of NOX activity was considered to have therapeutic potential. One of the possible outcomes of anticancer therapy, which has recently gained much interest, is cancer cell senescence. The induction of senescence leads to prolonged inhibition of proliferation and contributes to tumor growth restriction. The aim of our studies was to investigate the influence of low, non-toxic doses of diphenyleneiodonium chloride (DPI), a potent inhibitor of flavoenzymes including NADPH oxidases, on p53-proficient and p53-deficient HCT116 human colon cancer cells and MCF-7 breast cancer cells. We demonstrated that the temporal treatment of HCT116 and MCF-7 cancer cells (both p53 wild-type) with DPI caused induction of senescence, that was correlated with decreased level of ROS and upregulation of p53/p21 proteins. On the contrary, in the case of p53−/− HCT116 cells, apoptosis was shown to be the prevailing effect of DPI treatment. Thus, our studies provided a proof that inhibiting ROS production, and by this means influencing ROS sensitive pathways, remains an alternative strategy to facilitate so called therapy-induced senescence in cancers.
Katarzyna Piszczatowska; Dorota Przybylska; Ewa Sikora; Grażyna Mosieniak. Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells. Antioxidants 2020, 9, 1248 .
AMA StyleKatarzyna Piszczatowska, Dorota Przybylska, Ewa Sikora, Grażyna Mosieniak. Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells. Antioxidants. 2020; 9 (12):1248.
Chicago/Turabian StyleKatarzyna Piszczatowska; Dorota Przybylska; Ewa Sikora; Grażyna Mosieniak. 2020. "Inhibition of NADPH Oxidases Activity by Diphenyleneiodonium Chloride as a Mechanism of Senescence Induction in Human Cancer Cells." Antioxidants 9, no. 12: 1248.
Polyploid somatic cells have ‘programmed’ roles in normal development and stress responses. Transient polyploidy states have been observed in several tumor types at early stages of tumorigenesis. They can give rise to the aneuploidy state which is a common feature of human cancer cells. Similarly, to cancer development, cancer treatment can lead to transient polyploidy. Polyploid giant cells (PGCCs) in cancer are often associated with poor prognosis and disease relapse. Cancer cell senescence- a proliferation arrest accompanied by a set of characteristic markers- induced by therapy is also associated with transient polyploidy formation and cancer relapse. The question is whether therapy-induced senescence (TIS) and therapy induced polyploidy (TIP) are mechanistically or coincidentally connected. This problem needs to be solved rather urgently, because TIS appears to be more common phenomena than originally believed. Another arising question concerns reversibility of cancer cell senescence as a consequence of atypical divisions of polyploid cells. In our review we will try to answer this fundamental question by referring to published literature and to our own studies.
Ewa Sikora; Joanna Czarnecka-Herok; Agnieszka Bojko; Piotr Sunderland. Therapy-induced polyploidization and senescence: Coincidence or interconnection? Seminars in Cancer Biology 2020, 1 .
AMA StyleEwa Sikora, Joanna Czarnecka-Herok, Agnieszka Bojko, Piotr Sunderland. Therapy-induced polyploidization and senescence: Coincidence or interconnection? Seminars in Cancer Biology. 2020; ():1.
Chicago/Turabian StyleEwa Sikora; Joanna Czarnecka-Herok; Agnieszka Bojko; Piotr Sunderland. 2020. "Therapy-induced polyploidization and senescence: Coincidence or interconnection?" Seminars in Cancer Biology , no. : 1.
The induction of senescence/polyploidization and their role in cancer recurrence is still a poorly explored issue. We showed that MDA-MB-231 and MCF-7 breast cancer cells underwent reversible senescence/polyploidization upon pulse treatment with doxorubicin (dox). Subsequently, senescent/polyploid cells produced progeny (escapers) that possessed the same amount of DNA as parental cells. In a dox-induced senescence/polyploidization state, the accumulation of autophagy protein markers, such as LC3B II and p62/SQSTM1, was observed. However, the senescent cells were characterized by a very low rate of new autophagosome formation and degradation, estimated by autophagic index. In contrast to senescent cells, escapers had a substantially increased autophagic index and transcription factor EB activation, but a decreased level of an autophagy inhibitor, Rubicon, and autophagic vesicles with non-degraded cargo. These results strongly suggested that autophagy in escapers was improved, especially in MDA-MB-231 cells. The escapers of both cell lines were also susceptible to dox-induced senescence. However, MDA-MB-231 cells which escaped from senescence were characterized by a lower number of γH2AX foci and a different pattern of interleukin synthesis than senescent cells. Thus, our studies showed that breast cancer cells can undergo senescence uncoupled from autophagy status, but autophagic flux resumption may be indispensable in cancer cell escape from senescence/polyploidy.
Agnieszka Bojko; Karolina Staniak; Joanna Czarnecka-Herok; Piotr Sunderland; Magdalena Dudkowska; Małgorzata Alicja Śliwińska; Kristine Salmina; Ewa Sikora. Improved Autophagic Flux in Escapers from Doxorubicin-Induced Senescence/Polyploidy of Breast Cancer Cells. International Journal of Molecular Sciences 2020, 21, 6084 .
AMA StyleAgnieszka Bojko, Karolina Staniak, Joanna Czarnecka-Herok, Piotr Sunderland, Magdalena Dudkowska, Małgorzata Alicja Śliwińska, Kristine Salmina, Ewa Sikora. Improved Autophagic Flux in Escapers from Doxorubicin-Induced Senescence/Polyploidy of Breast Cancer Cells. International Journal of Molecular Sciences. 2020; 21 (17):6084.
Chicago/Turabian StyleAgnieszka Bojko; Karolina Staniak; Joanna Czarnecka-Herok; Piotr Sunderland; Magdalena Dudkowska; Małgorzata Alicja Śliwińska; Kristine Salmina; Ewa Sikora. 2020. "Improved Autophagic Flux in Escapers from Doxorubicin-Induced Senescence/Polyploidy of Breast Cancer Cells." International Journal of Molecular Sciences 21, no. 17: 6084.
ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A–Telangiectasia disease (A–T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A–T, we have focused on senescence of neural progenitor cells (NPCs) derived from A–T reprogrammed fibroblasts. Accordingly, A–T NPCs obtained through neural differentiation of iPSCs in 5% oxygen possessed some features of senescence including increased activity of SA-β-gal and secretion of IL6 and IL8 in comparison to control NPCs. This phenotype of A–T NPC was accompanied by elevated oxidative stress. A–T NPCs exhibited symptoms of impaired autophagy and mitophagy with lack of response to chloroquine treatment. Additional sources of oxidative stress like increased oxygen concentration (20 %) and H2O2 respectively aggravated the phenotype of senescence and additionally disturbed the process of mitophagy. In both cases only A–T NPCs reacted to the treatment. We conclude that oxidative stress may be responsible for the phenotype of senescence and impairment of autophagy in A–T NPCs. Our results point to senescent A–T cells as a potential therapeutic target in this disease.
Piotr Sunderland; Justyna Augustyniak; Jacek Lenart; Leonora Bużańska; Luigi Carlessi; Domenico Delia; Ewa Sikora. ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy. Mechanisms of Ageing and Development 2020, 190, 111296 .
AMA StylePiotr Sunderland, Justyna Augustyniak, Jacek Lenart, Leonora Bużańska, Luigi Carlessi, Domenico Delia, Ewa Sikora. ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy. Mechanisms of Ageing and Development. 2020; 190 ():111296.
Chicago/Turabian StylePiotr Sunderland; Justyna Augustyniak; Jacek Lenart; Leonora Bużańska; Luigi Carlessi; Domenico Delia; Ewa Sikora. 2020. "ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy." Mechanisms of Ageing and Development 190, no. : 111296.
The regular use of medication may interfere with micronutrient metabolism on several levels, such as absorption, turnover rate, and tissue distribution, and this might be amplified during aging. This study evaluates the impact of self-reported medication intake on plasma micronutrients in the MARK-AGE Project, a cross-sectional observational study in 2217 subjects (age- and sex-stratified) aged 35–75 years from six European countries that were grouped according to age. Polypharmacy as possible determinant of micronutrient concentrations was assessed using multiple linear regression models adjusted for age-group, dietary fruit, vegetables, and juice intake, and other confounders. Younger participants reported taking fewer drugs than older participants. Inverse associations between medication intake and lutein (−3.31% difference per increase in medication group), β-carotene (−11.44%), α-carotene (−8.50%) and positive associations with retinol (+2.26%), α-tocopherol/cholesterol (+2.89%) and γ-tocopherol/cholesterol (+1.36%) occurred in multiple adjusted regression models. Combined usage of a higher number of medical drugs was associated with poorer status of carotenoids on the one hand and higher plasma concentrations of retinol, α- and γ-tocopherol on the other hand. Our results raise concerns regarding the safety of drug combinations via the significant and surprisingly multifaceted disturbance of the concentrations of relevant micronutrients.
Daniela Weber; Bastian Kochlik; Wolfgang Stuetz; Martijn E. T. Dollé; Eugène H. J. M. Jansen; Beatrix Grubeck-Loebenstein; Florence Debacq-Chainiaux; Jürgen Bernhardt; Efstathios S. Gonos; Miriam Capri; Claudio Franceschi; Ewa Sikora; María Moreno-Villanueva; Alexander Bürkle; Tilman Grune. Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals. Journal of Clinical Medicine 2020, 9, 2072 .
AMA StyleDaniela Weber, Bastian Kochlik, Wolfgang Stuetz, Martijn E. T. Dollé, Eugène H. J. M. Jansen, Beatrix Grubeck-Loebenstein, Florence Debacq-Chainiaux, Jürgen Bernhardt, Efstathios S. Gonos, Miriam Capri, Claudio Franceschi, Ewa Sikora, María Moreno-Villanueva, Alexander Bürkle, Tilman Grune. Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals. Journal of Clinical Medicine. 2020; 9 (7):2072.
Chicago/Turabian StyleDaniela Weber; Bastian Kochlik; Wolfgang Stuetz; Martijn E. T. Dollé; Eugène H. J. M. Jansen; Beatrix Grubeck-Loebenstein; Florence Debacq-Chainiaux; Jürgen Bernhardt; Efstathios S. Gonos; Miriam Capri; Claudio Franceschi; Ewa Sikora; María Moreno-Villanueva; Alexander Bürkle; Tilman Grune. 2020. "Medication Intake Is Associated with Lower Plasma Carotenoids and Higher Fat-Soluble Vitamins in the Cross-Sectional MARK-AGE Study in Older Individuals." Journal of Clinical Medicine 9, no. 7: 2072.
Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of TP53-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-MB-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.
Kristine Salmina; Agnieszka Bojko; Inna Inashkina; Karolina Staniak; Magdalena Dudkowska; Petar Podlesniy; Felikss Rumnieks; Ninel M Vainshelbaum; Dace Pjanova; Ewa Sikora; Jekaterina Erenpreisa. “Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres. International Journal of Molecular Sciences 2020, 21, 2779 .
AMA StyleKristine Salmina, Agnieszka Bojko, Inna Inashkina, Karolina Staniak, Magdalena Dudkowska, Petar Podlesniy, Felikss Rumnieks, Ninel M Vainshelbaum, Dace Pjanova, Ewa Sikora, Jekaterina Erenpreisa. “Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres. International Journal of Molecular Sciences. 2020; 21 (8):2779.
Chicago/Turabian StyleKristine Salmina; Agnieszka Bojko; Inna Inashkina; Karolina Staniak; Magdalena Dudkowska; Petar Podlesniy; Felikss Rumnieks; Ninel M Vainshelbaum; Dace Pjanova; Ewa Sikora; Jekaterina Erenpreisa. 2020. "“Mitotic Slippage” and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres." International Journal of Molecular Sciences 21, no. 8: 2779.
Rational drug design and in vitro pharmacology profiling constitute the gold standard in drug development pipelines. Problems arise, however, because this process is often difficult due to limited information regarding the complete identification of a molecule’s biological activities. The increasing affordability of genome-wide next-generation technologies now provides an excellent opportunity to understand a compound’s diverse effects on gene regulation. Here, we used an unbiased approach in lung and colon cancer cell lines to identify the early transcriptomic signatures of C-1305 cytotoxicity that highlight the novel pathways responsible for its biological activity. Our results demonstrate that C-1305 promotes direct microtubule stabilization as a part of its mechanism of action that leads to apoptosis. Furthermore, we show that C-1305 promotes G2 cell cycle arrest by modulating gene expression. The results indicate that C-1305 is the first microtubule stabilizing agent that also is a topoisomerase II inhibitor. This study provides a novel approach and methodology for delineating the antitumor mechanisms of other putative anticancer drug candidates.
Jarosław Króliczewski; Sylwia Bartoszewska; Magdalena Dudkowska; Dorota Janiszewska; Agnieszka Biernatowska; David K. Crossman; Karol Krzymiński; Małgorzata Wysocka; Anna Romanowska; Maciej Baginski; Michal Markuszewski; Renata J. Ochocka; James F. Collawn; Aleksander F. Sikorski; Ewa Sikora; Rafal Bartoszewski. Utilizing Genome-Wide mRNA Profiling to Identify the Cytotoxic Chemotherapeutic Mechanism of Triazoloacridone C-1305 as Direct Microtubule Stabilization. Cancers 2020, 12, 864 .
AMA StyleJarosław Króliczewski, Sylwia Bartoszewska, Magdalena Dudkowska, Dorota Janiszewska, Agnieszka Biernatowska, David K. Crossman, Karol Krzymiński, Małgorzata Wysocka, Anna Romanowska, Maciej Baginski, Michal Markuszewski, Renata J. Ochocka, James F. Collawn, Aleksander F. Sikorski, Ewa Sikora, Rafal Bartoszewski. Utilizing Genome-Wide mRNA Profiling to Identify the Cytotoxic Chemotherapeutic Mechanism of Triazoloacridone C-1305 as Direct Microtubule Stabilization. Cancers. 2020; 12 (4):864.
Chicago/Turabian StyleJarosław Króliczewski; Sylwia Bartoszewska; Magdalena Dudkowska; Dorota Janiszewska; Agnieszka Biernatowska; David K. Crossman; Karol Krzymiński; Małgorzata Wysocka; Anna Romanowska; Maciej Baginski; Michal Markuszewski; Renata J. Ochocka; James F. Collawn; Aleksander F. Sikorski; Ewa Sikora; Rafal Bartoszewski. 2020. "Utilizing Genome-Wide mRNA Profiling to Identify the Cytotoxic Chemotherapeutic Mechanism of Triazoloacridone C-1305 as Direct Microtubule Stabilization." Cancers 12, no. 4: 864.
Torquetenovirus (TTV) viremia has been associated with increased mortality risk in the elderly population. This work aims to investigate TTV viremia as a potential biomarker of immunosenescence. We compared levels of circulating TTV in 1813 participants of the MARK-AGE project, including human models of delayed (offspring of centenarians [GO]) and premature (Down syndrome [DS]) immunosenescence. The TTV load was positively associated with age, cytomegalovirus (CMV) antibody levels, and the Cu/Zn ratio and negatively associated with platelets, total cholesterol, and total IgM. TTV viremia was highest in DS and lowest in GO, with intermediate levels in the SGO (spouses of GO) and RASIG (Randomly Recruited Age-Stratified Individuals From The General Population) populations. In the RASIG population, TTV DNA loads showed a slight negative association with CD3+T-cells and CD4+T-cells. Finally, males with ≥4log TTV copies/mL had a higher risk of having a CD4/CD8 ratio<1 than those with lower viremia (odds ratio [OR] = 2.85, 95% confidence interval [CI]: 1.06–7.62), as well as reduced CD3+ and CD4+T-cells compared to males with lower replication rates (<4log), even after adjusting for CMV infection. In summary, differences in immune system preservation are reflected in the models of delayed and premature immunosenescence, displaying the best and worst control over TTV replication, respectively. In the general population, TTV loads were negatively associated with CD4+ cell counts, with an increased predisposition for an inverted CD4/CD8 ratio for individuals with TTV loads ≥4log copies/mL, thus promoting an immune risk phenotype.
Robertina Giacconi; Fabrizio Maggi; Lisa Macera; Pietro Giorgio Spezia; Mauro Pistello; Mauro Provinciali; Francesco Piacenza; Andrea Basso; Alexander Bürkle; María Moreno-Villanueva; Martijn E T Dollé; Eugène Jansen; Tilman Grune; Wolfgang Stuetz; Efstathios S Gonos; Christiane Schön; Jürgen Bernhardt; Beatrix Grubeck-Loebenstein; Ewa Sikora; Magdalena Dudkowska; Dorota Janiszewska; Olivier Toussaint; Florence Debacq- Chainiaux; Claudio Franceschi; Miriam Capri; Antti Hervonen; Mikko Hurme; Eline Slagboom; Nicolle Breusing; Eugenio Mocchegiani; Marco Malavolta. Prevalence and Loads of Torquetenovirus in the European MARK-AGE Study Population. The Journals of Gerontology: Series A 2019, 75, 1838 -1845.
AMA StyleRobertina Giacconi, Fabrizio Maggi, Lisa Macera, Pietro Giorgio Spezia, Mauro Pistello, Mauro Provinciali, Francesco Piacenza, Andrea Basso, Alexander Bürkle, María Moreno-Villanueva, Martijn E T Dollé, Eugène Jansen, Tilman Grune, Wolfgang Stuetz, Efstathios S Gonos, Christiane Schön, Jürgen Bernhardt, Beatrix Grubeck-Loebenstein, Ewa Sikora, Magdalena Dudkowska, Dorota Janiszewska, Olivier Toussaint, Florence Debacq- Chainiaux, Claudio Franceschi, Miriam Capri, Antti Hervonen, Mikko Hurme, Eline Slagboom, Nicolle Breusing, Eugenio Mocchegiani, Marco Malavolta. Prevalence and Loads of Torquetenovirus in the European MARK-AGE Study Population. The Journals of Gerontology: Series A. 2019; 75 (10):1838-1845.
Chicago/Turabian StyleRobertina Giacconi; Fabrizio Maggi; Lisa Macera; Pietro Giorgio Spezia; Mauro Pistello; Mauro Provinciali; Francesco Piacenza; Andrea Basso; Alexander Bürkle; María Moreno-Villanueva; Martijn E T Dollé; Eugène Jansen; Tilman Grune; Wolfgang Stuetz; Efstathios S Gonos; Christiane Schön; Jürgen Bernhardt; Beatrix Grubeck-Loebenstein; Ewa Sikora; Magdalena Dudkowska; Dorota Janiszewska; Olivier Toussaint; Florence Debacq- Chainiaux; Claudio Franceschi; Miriam Capri; Antti Hervonen; Mikko Hurme; Eline Slagboom; Nicolle Breusing; Eugenio Mocchegiani; Marco Malavolta. 2019. "Prevalence and Loads of Torquetenovirus in the European MARK-AGE Study Population." The Journals of Gerontology: Series A 75, no. 10: 1838-1845.
It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-MB-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.
Agnieszka Bojko; Joanna Czarnecka-Herok; Agata Charzynska; Michal Dabrowski; Ewa Sikora. Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents. Cells 2019, 8, 1501 .
AMA StyleAgnieszka Bojko, Joanna Czarnecka-Herok, Agata Charzynska, Michal Dabrowski, Ewa Sikora. Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents. Cells. 2019; 8 (12):1501.
Chicago/Turabian StyleAgnieszka Bojko; Joanna Czarnecka-Herok; Agata Charzynska; Michal Dabrowski; Ewa Sikora. 2019. "Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents." Cells 8, no. 12: 1501.
Senotherapy is an antiageing strategy. It refers to selective killing of senescent cells by senolytic agents, strengthening the activity of immune cells that eliminate senescent cells or alleviating the secretory phenotype (SASP) of senescent cells. As senescent cells accumulate with age and are considered to be at the root of age-related disorders, senotherapy seems to be very promising in improving healthspan. Genetic approaches, which allowed to selectively induce death of senescent cells in transgenic mice, provided proof-of-concept evidence that elimination of senescent cells can be a therapeutic approach for treating many age-related diseases. Translating these results into humans is based on searching for synthetic and natural compounds, which are able to exert such beneficial effects. The major challenge in the field is to show efficacy, safety and tolerability of senotherapy in humans. The question is how these therapeutics can influence senescence of non-dividing post-mitotic cells. Another issue concerns senescence of cancer cells induced during therapy as there is a risk of resumption of senescent cell division that could terminate in cancer renewal. Thus, development of an effective senotherapeutic strategy is also an urgent issue in cancer treatment. Different aspects, both beneficial and potentially detrimental, will be discussed in this review.
Ewa Sikora; Anna Bielak-Zmijewska; Grazyna Mosieniak. Targeting normal and cancer senescent cells as a strategy of senotherapy. Ageing Research Reviews 2019, 55, 100941 .
AMA StyleEwa Sikora, Anna Bielak-Zmijewska, Grazyna Mosieniak. Targeting normal and cancer senescent cells as a strategy of senotherapy. Ageing Research Reviews. 2019; 55 ():100941.
Chicago/Turabian StyleEwa Sikora; Anna Bielak-Zmijewska; Grazyna Mosieniak. 2019. "Targeting normal and cancer senescent cells as a strategy of senotherapy." Ageing Research Reviews 55, no. : 100941.
Trimethylamine-N-oxide (TMAO) has been suggested as a marker and mediator of cardiovascular diseases. However, data are contradictory, and the mechanisms are obscure. Strikingly, the role of the TMAO precursor trimethylamine (TMA) has not drawn attention in cardiovascular studies even though toxic effects of TMA were proposed several decades ago. We assessed plasma TMA and TMAO levels in healthy humans (HH) and cardiovascular patients qualified for aortic valve replacement (CP). The cytotoxicity of TMA and TMAO in rat cardiomyocytes was evaluated using an MTT test. The effects of TMA and TMAO on albumin and lactate dehydrogenase (LDH) were assessed using fluorescence correlation spectroscopy. In comparison to HH, CP had a two-fold higher plasma TMA (p < 0.001) and a trend towards higher plasma TMAO (p = 0.07). In CP plasma, TMA was inversely correlated with an estimated glomerular filtration rate (eGFR, p = 0.002). TMA but not TMAO reduced cardiomyocytes viability. Incubation with TMA but not TMAO resulted in the degradation of the protein structure of LDH and albumin. In conclusion, CP show increased plasma TMA, which is inversely correlated with eGFR. TMA but not TMAO exerts negative effects on cardiomyocytes, likely due to its disturbing effect on proteins. Therefore, TMA but not TMAO may be a toxin and a marker of cardiovascular risk.
Kinga Jaworska; Dagmara Hering; Grażyna Mosieniak; Anna Bielak-Zmijewska; Marta Pilz; Michał Konwerski; Aleksandra Gasecka; Agnieszka Kapłon-Cieślicka; Krzysztof Filipiak; Ewa Sikora; Robert Hołyst; Marcin Ufnal. TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology. Toxins 2019, 11, 490 .
AMA StyleKinga Jaworska, Dagmara Hering, Grażyna Mosieniak, Anna Bielak-Zmijewska, Marta Pilz, Michał Konwerski, Aleksandra Gasecka, Agnieszka Kapłon-Cieślicka, Krzysztof Filipiak, Ewa Sikora, Robert Hołyst, Marcin Ufnal. TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology. Toxins. 2019; 11 (9):490.
Chicago/Turabian StyleKinga Jaworska; Dagmara Hering; Grażyna Mosieniak; Anna Bielak-Zmijewska; Marta Pilz; Michał Konwerski; Aleksandra Gasecka; Agnieszka Kapłon-Cieślicka; Krzysztof Filipiak; Ewa Sikora; Robert Hołyst; Marcin Ufnal. 2019. "TMA, A Forgotten Uremic Toxin, but Not TMAO, Is Involved in Cardiovascular Pathology." Toxins 11, no. 9: 490.
It has been suggested that trimethylamine oxide (TMAO), a liver oxygenation product of gut bacteria-produced trimethylamine (TMA), is a marker of cardiovascular risk. However, mechanisms of the increase and biological effects of TMAO are obscure. Furthermore, the potential role of TMAO precursor, that is TMA, has not been investigated. We evaluated the effect of age, a cardiovascular risk factor, on plasma levels of TMA and TMAO, gut bacteria composition, gut-to-blood penetration of TMA, histological and hemodynamic parameters in 3-month-old and 18-month-old, male, Sprague–Dawley and Wistar–Kyoto rats. Cytotoxicity of TMA and TMAO was studied in human vascular smooth muscle cells. Older rats showed significantly different gut bacteria composition, a significantly higher gut-to-blood TMA penetration, and morphological and hemodynamic alterations in intestines. In vitro, TMA at concentration of 500 µmol/L (2-fold higher than in portal blood) decreased human vascular smooth muscle cells viability. In contrast, TMAO at 1,000-fold higher concentration than physiological one had no effect on human vascular smooth muscle cells viability. In conclusion, older rats show higher plasma level of TMA due to a “leaky gut”. TMA but not TMAO affects human vascular smooth muscle cells viability. We propose that TMA but not TMAO may be a marker and mediator of cardiovascular risk.
Kinga Jaworska; Marek Konop; Tomasz Hutsch; Karol Perlejewski; Marek Radkowski; Marta Grochowska; Anna Bielak-Zmijewska; Grazyna Mosieniak; Ewa Sikora; Marcin Ufnal. Trimethylamine But Not Trimethylamine Oxide Increases With Age in Rat Plasma and Affects Smooth Muscle Cells Viability. The Journals of Gerontology: Series A 2019, 75, 1276 -1283.
AMA StyleKinga Jaworska, Marek Konop, Tomasz Hutsch, Karol Perlejewski, Marek Radkowski, Marta Grochowska, Anna Bielak-Zmijewska, Grazyna Mosieniak, Ewa Sikora, Marcin Ufnal. Trimethylamine But Not Trimethylamine Oxide Increases With Age in Rat Plasma and Affects Smooth Muscle Cells Viability. The Journals of Gerontology: Series A. 2019; 75 (7):1276-1283.
Chicago/Turabian StyleKinga Jaworska; Marek Konop; Tomasz Hutsch; Karol Perlejewski; Marek Radkowski; Marta Grochowska; Anna Bielak-Zmijewska; Grazyna Mosieniak; Ewa Sikora; Marcin Ufnal. 2019. "Trimethylamine But Not Trimethylamine Oxide Increases With Age in Rat Plasma and Affects Smooth Muscle Cells Viability." The Journals of Gerontology: Series A 75, no. 7: 1276-1283.
Curcumin, a phytochemical present in the spice named turmeric, and one of the promising anti-aging factors, is itself able to induce cellular senescence. We have recently shown that cells building the vasculature senesced as a result of curcumin treatment. Curcumin-induced senescence was DNA damage-independent; however, activation of ATM was observed. Moreover, neither increased ROS production, nor even ATM were indispensable for senescence progression. In this paper we tried to elucidate the mechanism of curcumin-induced senescence. We analyzed the time-dependence of the level and activity of numerous proteins involved in senescence progression in vascular smooth muscle cells and how inhibition p38 or p38 together with ATM, two proteins involved in canonical signaling pathways, influenced cell senescence. We showed that curcumin was able to influence many signaling pathways of which probably none was dominant and sufficient to induce senescence by itself. However, we cannot exclude that the switch between initiation and progression of senescence is the result of the impact of curcumin on signaling pathways engaging AMPK, ATM, sirtuin 1 and p300 and on their reciprocal interplay. Cytostatic concentration of curcumin induced cellular stress, which exceeded the adaptive response and, in consequence, led to cellular senescence, which is triggered by time dependent activation of several signaling pathways playing diverse roles in different phases of senescence progression. We also showed that activity of β-glucuronidase, the enzyme involved in deconjugation of the main metabolites of curcumin, glucuronides, increased in senescent cells. It suggests a possible local elevation of curcumin concentration in the organism.
Wioleta Grabowska; Grażyna Mosieniak; Natalia Achtabowska; Robert Czochara; Grzegorz Litwinienko; Agnieszka Bojko; Ewa Sikora; Anna Bielak-Zmijewska. Curcumin induces multiple signaling pathways leading to vascular smooth muscle cell senescence. Biogerontology 2019, 20, 783 -798.
AMA StyleWioleta Grabowska, Grażyna Mosieniak, Natalia Achtabowska, Robert Czochara, Grzegorz Litwinienko, Agnieszka Bojko, Ewa Sikora, Anna Bielak-Zmijewska. Curcumin induces multiple signaling pathways leading to vascular smooth muscle cell senescence. Biogerontology. 2019; 20 (6):783-798.
Chicago/Turabian StyleWioleta Grabowska; Grażyna Mosieniak; Natalia Achtabowska; Robert Czochara; Grzegorz Litwinienko; Agnieszka Bojko; Ewa Sikora; Anna Bielak-Zmijewska. 2019. "Curcumin induces multiple signaling pathways leading to vascular smooth muscle cell senescence." Biogerontology 20, no. 6: 783-798.
The elimination of expanded T cells at the end of immune response is crucial to maintain homeostasis and avoid any uncontrolled inflammation. Resting mature T lymphocytes when activated via their antigen-specific receptor (TCR) and CD28 coreceptor start to proliferate and acquire resistance to apoptosis. Reactivation of T cells induces expression of CD95L, which after binding to CD95 surface-expressed death receptor, triggers signaling pathway to apoptosis. The process is called activation-induced cell death (AICD). In executing AICD, receptor-dependent apoptotic pathway overlaps with mitochondrial signaling to apoptosis. Immunosenescence leads to the shrinkage of T cell repertoire due to the reduction of naïve cells and accumulation of oligoclonal CD8+ and, to a lower extent, CD4+ cells, which are mainly CD95-positive and CD28-negative. CD28− cells dominate not only in elderly people, but their presence has also been linked to autoimmune disease, AIDS, and age-related disorders or decreased efficacy of vaccination. Propensity of CD28− cells to undergo AICD, and generally, apoptosis changes with age. However, collected data so far are inconclusive as they show an increased, unchanged, or decreased propensity to apoptosis in the elderly in comparison with young individuals. Recently, a definite involvement of autophagy and necroptosis in homeostasis of T cells has been recognized; however, their role in the termination of the adaptive immune response is still poorly known, especially in aging. However, it can be expected that future studies on necroptotic and autophagic cell death will clarify the so far inconsistent data concerning age-dependent changes in AICD.
Ewa Sikora; Agnieszka Brzezińska. Activation-Induced Cell Death of T Cells in Human Aging. Handbook of Immunosenescence 2019, 533 -552.
AMA StyleEwa Sikora, Agnieszka Brzezińska. Activation-Induced Cell Death of T Cells in Human Aging. Handbook of Immunosenescence. 2019; ():533-552.
Chicago/Turabian StyleEwa Sikora; Agnieszka Brzezińska. 2019. "Activation-Induced Cell Death of T Cells in Human Aging." Handbook of Immunosenescence , no. : 533-552.
Recently, Weber et al. published a thorough investigation of the age-dependency of oxidative stress (OS) determined by the steady state concentrations of different compounds - oxidation products and antioxidants - that are in common use as biomarkers of OS in 2207 healthy individuals of the cross-sectional MARK-AGE Project. The correlations among biomarkers were significant but weak. These findings may indicate different manifestations of OS and must further be evaluated. Here, we report a refined analysis of OS based on the above-mentioned original data. We show that malondialdehyde (MDA) appears to be sensitive to both gender and age. It is significantly lower and shows a greater age-dependence in women than in men. The age-dependency of MDA in women arises in a stepwise fashion. The age-dependent slope of the steady state concentration is maximal at the age between 50 and 55 years, indicating that it may be attributed to the change of metabolism in the post-menopause. Interestingly, total glutathione (GSH) decreased with age simultaneously with the increase in MDA. Different biomarkers yield different gender- and age-dependencies. Unlike the concentration of MDA, the concentrations of the other two oxidation products, i.e. protein carbonyls and 3-nitrotyrosine were similar in men and women and appeared to be independent of age in the healthy study population. The analyzed antioxidants exhibited different gender- and age-dependencies. In conclusion, it appears that all the biomarkers assessed here reflect different types of OS and that MDA and GSH reflect the same type of OS.
Ilya Pinchuk; Daniela Weber; Bastian Kochlik; Wolfgang Stuetz; Olivier Toussaint; Florence Debacq-Chainiaux; Martijn E.T. Dollé; Eugène H.J.M. Jansen; Efstathios S. Gonos; Ewa Sikora; Nicolle Breusing; Daniela Gradinaru; Thilo Sindlinger; María Moreno-Villanueva; Alexander Bürkle; Tilman Grune; Dov Lichtenberg. Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study. Redox Biology 2019, 24, 101204 .
AMA StyleIlya Pinchuk, Daniela Weber, Bastian Kochlik, Wolfgang Stuetz, Olivier Toussaint, Florence Debacq-Chainiaux, Martijn E.T. Dollé, Eugène H.J.M. Jansen, Efstathios S. Gonos, Ewa Sikora, Nicolle Breusing, Daniela Gradinaru, Thilo Sindlinger, María Moreno-Villanueva, Alexander Bürkle, Tilman Grune, Dov Lichtenberg. Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study. Redox Biology. 2019; 24 ():101204.
Chicago/Turabian StyleIlya Pinchuk; Daniela Weber; Bastian Kochlik; Wolfgang Stuetz; Olivier Toussaint; Florence Debacq-Chainiaux; Martijn E.T. Dollé; Eugène H.J.M. Jansen; Efstathios S. Gonos; Ewa Sikora; Nicolle Breusing; Daniela Gradinaru; Thilo Sindlinger; María Moreno-Villanueva; Alexander Bürkle; Tilman Grune; Dov Lichtenberg. 2019. "Gender- and age-dependencies of oxidative stress, as detected based on the steady state concentrations of different biomarkers in the MARK-AGE study." Redox Biology 24, no. : 101204.
It is believed that postponing ageing is more effective and less expensive than the treatment of particular age-related diseases. Compounds which could delay symptoms of ageing, especially natural products present in a daily diet, are intensively studied. One of them is curcumin. It causes the elongation of the lifespan of model organisms, alleviates ageing symptoms and postpones the progression of age-related diseases in which cellular senescence is directly involved. It has been demonstrated that the elimination of senescent cells significantly improves the quality of life of mice. There is a continuous search for compounds, named senolytic drugs, that selectively eliminate senescent cells from organisms. In this paper, we endeavor to review the current knowledge about the anti-ageing role of curcumin and discuss its senolytic potential.
Anna Bielak-Zmijewska; Wioleta Grabowska; Agata Ciolko; Agnieszka Bojko; Grażyna Mosieniak; Łukasz Bijoch; Ewa Sikora. The Role of Curcumin in the Modulation of Ageing. International Journal of Molecular Sciences 2019, 20, 1239 .
AMA StyleAnna Bielak-Zmijewska, Wioleta Grabowska, Agata Ciolko, Agnieszka Bojko, Grażyna Mosieniak, Łukasz Bijoch, Ewa Sikora. The Role of Curcumin in the Modulation of Ageing. International Journal of Molecular Sciences. 2019; 20 (5):1239.
Chicago/Turabian StyleAnna Bielak-Zmijewska; Wioleta Grabowska; Agata Ciolko; Agnieszka Bojko; Grażyna Mosieniak; Łukasz Bijoch; Ewa Sikora. 2019. "The Role of Curcumin in the Modulation of Ageing." International Journal of Molecular Sciences 20, no. 5: 1239.