Mitomycin C induced genotoxic stress in endothelial cells is associated with differential expression of proinflammatory cytokines

Sinitsky, M. Yu.; Kutikhin, Anton G.; Цепокина, А. В.; Шишкова, Д. К.; Asanov, Maxim А.; Yuzhalin, Arseniy E.; Минина, В. И.; Понасенко, А. В.

doi:10.1016/j.mrgentox.2020.503252

Cited by 22 publications

(17 citation statements)

References 64 publications

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“…At the same time, recently it was reported that genotoxic stress can also trigger the pathological activation of endothelium and the formation of a proatherosclerotic phenotype by endothelial cells. Our previously published results demonstrated that endothelial cells in vitro exposed to 500 ng/mL alkylating mutagen MMC can trigger severe genotoxic but not cytotoxic effects in endothelial cells [ 8 ] accompanied with the increased mRNA level of genes involved in the proinflammatory activation of endothelium (endothelial proinflammatory cytokines IL6 and CXCL8 , endothelial cell receptors to leukocytes VCAM1 , ICAM1, and SELE ), impaired endothelial mechanotransduction ( KLF4 ) and endothelial-to-mesenchymal transition ( SNAI1 , SNAI2, and TWIST1 ) [ 8 , 9 ] and suggested as molecular markers of endothelial disfunction [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…It is known that endothelial disfunction underlying the atherogenesis and defined as a loss of functionality in terms of anti-inflammatory, anti-thrombotic, and vasodilatory abilities of endothelial cells [ 5 ] can be triggered by the various risk factors including low or non-laminar shear stress, metabolic, and chemical stress (diabetes mellitus, high serum cholesterol, or effects of cigarette smoke) [ 6 ]. Recently it was reported that genotoxic stress defined as a situation that initiates DNA damage compromising the cell’s genomic integrity leading to replication and transcription arrest [ 7 ] in endothelial cells in vitro exposed to alkylating mutagen mitomycin C (MMC) followed by DNA alkylation and DNA crosslinking can be considered as another risk factor for endothelial disfunction [ 8 , 9 ]. At the same time, the molecular mechanisms of genotoxic stress induced endothelial disfunction are still not clear [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

et al. 2022

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Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide. Endothelial disfunction underlying the atherogenesis can be triggered by genotoxic stress in endothelial cells. In the presented research whole transcriptome sequencing (RNA-seq) of human coronary artery (HCAEC) and internal thoracic artery (HITAEC) endothelial cells in vitro exposed to 500 ng/mL mitomycin C (treatment group) or 0.9% NaCl (control group) was performed. Resulting to bioinformatic analysis, 56 upregulated differentially expressed genes (DEGs) and 6 downregulated DEGs with absolute fold change ≥ 2 and FDR p-value < 0.05 were selected in HCAEC exposed to mitomycin C compared to the control group; in HITAEC only one upregulated DEG was found. According to Gene Ontology enrichment analysis, DEGs in HCAEC were classified into 25 functional groups of biological processes, while in HITAEC we found no statistically significant (FDR p-value < 0.05) groups. The four largest groups containing more than 50% DEGs (“signal transduction”, “response to stimulus”, “biological regulation”, and “regulation of biological process”) were identified. Finally, candidate DEGs and pathways underlying the genotoxic stress induced endothelial disfunction have been discovered that could improve our understanding of fundamental basis of atherogenesis and help to justification of genotoxic stress as a novel risk factor for atherosclerosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

et al. 2022

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“…MMC, an aziridine-containing agent derived from Streptomyces caespitosus or S. lavendulae, is used as a chemotherapeutic agent for tumors of various etiologies, as well as an experimental mutagen (14). The drug acts by two mechanisms: bioreductive alkylation of nucleic acids with the formation of DNA crosslinks, and by the generation of free radicals, such as superoxide and hydroxyl radicals, following metabolic activation (14,15). The main side effects of MMC are bone marrow suppression, pulmonary fibrosis, and kidney damage.…”

Section: Introductionmentioning

confidence: 99%

Study of Mutagenic and Antitoxic Properties of Gentabiferon-B

Shabunin

Gritsyuk

Востроилова

et al. 2022

Macedonian Veterinary Review

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The combination of immunomodulators and antibiotics in the treatment of animals with diseases of bacterial etiology is one of the effective strategies for animal therapy. The drug gentabiferon-B combines antibiotic gentamicin and species-specific (bovine) recombinant interferons -α and -γ. The study aimed to evaluate the effect of course application of gentabiferon-B on the cytogenetic stability of bone marrow cells of outbred mice after administering mitomycin C (MMC). The proportion of polychromatophilic erythrocytes in the bone marrow was assessed. There was no effect of gentabiferon-B on the frequency of polychromatophilic erythrocytes with micronuclei in both healthy animals and mice with MMC-induced cytogenetic instability. The course application of gentabiferon-B before the administration of MMC led to an increase in the proportion of polychromatophilic erythrocytes (46.03±2.61%) which was non-significantly different than the negative control group. The administration of MMC alone caused a decrease in the proportion of polychromatophilic erythrocytes to 33.33±1.83%. The antitoxic effect of gentabiferon-B led to an increase in the level of polychromatophilic erythrocytes by 38.1% compared to the group that received only MMC. Studies have shown that gentabiferon-B does not have mutagenic activity and anticlastogenic properties, however, it reduces the toxic effect of MMC. In conclusion, it is indicative that gentabiferon-B has antitoxic properties and can be safely used in animal therapy.

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“…It has been used in the treatment of gastric, bladder, pancreatic, and colon cancer [3]. MMC was observed to induce genotoxic stress in human primary endothelial Polymers 2021, 13, 3839 2 of 18 cells [4]. Due to its stable cytogenetic activity, MMC is used as a model mutagen for in vivo and in vitro studies.…”

Section: Introductionmentioning

confidence: 99%

Assessment of the Antigenotoxic Effects of Alginate and ZnO/Alginate–Nanocomposites Extracted from Brown Alga Fucus vesiculosus in Mice

et al. 2021

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Mitomycin C (MMC) is an alkylating chemotherapy drug that could induce DNA damage and genetic alteration. It has been used as a model mutagen for in vivo and in vitro studies. The current study aimed to evaluate the protective role of Zinc oxide alginate–nanocomposites (ZnO-Alg/NCMs) against MMC–induced genotoxicity in mice. Animals were treated as follows: the control group, the groups treated with Algin (400 mg/kg b.w), the groups treated with ZnO-Alg/NCMs (400 mg/kg b.w), the group treated with MMC, and the groups treated with MMC plus Algin or ZnO-Alg/NCMs. Pre-treatment with Algin and ZnO-Alg/NCMs was repeated for one or seven days. Zinc oxide alginate-nanocomposites (ZnO-Alg/NCMs) were synthesized with the aim of incorporating the intrinsic properties of their constituents as an antigenotoxic substance. In this study, alginate was extracted from the brown marine alga Fucus vesiculosus, Zinc oxide nanoparticles were synthesized by using water extract of the same alga, and loaded in alginate to synthesize ZnO-Alg/NCMs. ZnO-NPs and ZnO-Alg/NCMs were characterized by TEM, SEM, EDX, and Zeta potential. The obtained results confirmed that by TEM and SEM, ZnO-NPs are rod shaped which modified, when loaded in alginate matrix, into spherical shape. The physical stability of ZnO-Alg/NCMs was reported to be higher than ZnO-NPs due to the presence of more negative charges on ZnO-Alg/NCMs. The EDX analysis indicated that the amount of zinc was higher in ZnO-NPs than ZnO-Alg/NCMs. The in vivo results showed that treatment with MMC induced genotoxic disturbances. The combined treatment with Algin and ZnO-Alg/NCMs succeeded in inducing significant protection against MMC. It could be concluded that ZnO-Algin/NCMs is a promising candidate to protect against MMC–induced genotoxicity.

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Mitomycin C induced genotoxic stress in endothelial cells is associated with differential expression of proinflammatory cytokines

Cited by 22 publications

References 64 publications

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

Identification of Key Genes and Pathways in Genotoxic Stress Induced Endothelial Dysfunction: Results of Whole Transcriptome Sequencing

Study of Mutagenic and Antitoxic Properties of Gentabiferon-B

Assessment of the Antigenotoxic Effects of Alginate and ZnO/Alginate–Nanocomposites Extracted from Brown Alga Fucus vesiculosus in Mice

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