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Systems toxicology assessment revealed the impact of graphenea??based materials on cell cycle regulators
摘要： Understanding the cellular and molecular toxicity of graphene and its derivatives is essential for their biomedical applications. Herein, gene expression profile of graphene-exposed cells was retrieved from the GEO database. Differentially expressed genes and their functional roles were then investigated through the pathway, protein-protein interaction network, and module analysis. High degree (hub) and high betweenness centrality (bottleneck) nodes were subsequently identified. The functional analysis of central genes indicated that these graphene-gene interactions could be of great value for further investigation. Accordingly, we also followed the expression of five hub-bottleneck genes in graphene-treated murine peritoneal macrophages and human breast cancer cell line by real-time PCR. The five hub-bottleneck genes related to graphene cytotoxicity; CDK1, CCNB1, PLK1, TOP2A, and CCNA2 were identified through network analysis, which were highly correlated with regulation of cell cycle processes. The module analysis indicated the cell cycle pathway to be the predominant one. Gene expression evaluation showed down-regulation of these genes in the macrophages and cancer cells treated with graphene. These results provided some new intuitions concerning the graphene-cell interactions and unveiled targeting critical cell cycle regulators. The present study indicated some toxic effects of graphene-based materials through systems toxicology assessment. Integrating gene expression and protein-protein interaction network may help explaining biological responses of graphene and lead to beneficial impacts in nanomedicine.
关键词： Cell cycle,Graphene,Protein-protein interaction network,Gene expression,Systems toxicology
更新于2025-09-23 15:19:57
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ARS2 is required for retinal progenitor cell S-phase progression and Müller glial cell fate specification.
摘要： During a developmental period that extends postnatally in the mouse, proliferating multipotent retinal progenitor cells produce one of seven major cell types (rod, cone, bipolar, horizontal, amacrine, ganglion, and Müller glial cells) as they exit the cell cycle in consecutive waves. Cell production in the retina is tightly regulated by intrinsic, extrinsic, spatial, and temporal cues and is coupled to the timing of cell cycle exit. ARS2 (also known as SRRT) is a component of the nuclear cap-binding complex involved in RNA Polymerase II transcription, and is required for cell cycle progression. We show that postnatal RPCs require ARS2 for proper progression through S phase, and ARS2 disruption leads to early exit from the cell cycle. Furthermore, we observe an increase in the proportion of cells expressing a rod photoreceptor marker, and a loss of Müller glia marker expression, indicating a role for ARS2 in regulating cell fate specification or differentiation. Knockdown of FLASH, which interacts with ARS2 and is required for cell cycle progression and 3’-end processing of replication-dependent histone transcripts, phenocopies ARS2 knockdown. These data implicate ARS2/FLASH-mediated histone mRNA processing in regulating RPC cell cycle kinetics and neuroglial cell fate specification during postnatal retinal development.
关键词： photoreceptor cells,Müller cells,retina,retinal progenitor cells,cell cycle,Ars2
更新于2025-09-19 17:15:36
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Synthesis of water soluble silicon phthacyanine, naphthalocyanine bearing pyridine groups and investigation of their DNA interaction, topoisomerase inhibition, cytotoxic effects and cell cycle arrest properties
摘要： In this work, axially [3,5-bis(3-pyridin-4-ylpropoxy)phenyl]methoxy groups substituted silicon (IV) phthalocyanine 2, napthalocyanine 3 and their water soluble derivatives 2a, 3a were synthesized and DNA interaction, topoisomerases inhibitory properties, cytotoxicity against five carcinoma cell lines of water soluble derivatives were examined. The calf thymus DNA (CT-DNA) binding properties of 2a and 3a were monitored using UV-Vis spectroscopy and agarose gel electrophoresis. The results showed that the compounds interacted to CT-DNA via intercalation with Kb values of 3.94 ± (0.15) ×106 and 1.08 ± (0.10) ×105 M-1. In DNA cleavage studies, the compounds cleaved to supercoiled pBR322 plasmid DNA significantly with irradiation as compared to without irradiation. The results of topoisomerases studies claimed that both compounds had inhibitory effects against topoisomerases. In the cytotoxicity studies, the CC50 values of the compounds were found in range of 2.15-52.97 μM against to five carcinoma cell lines. The SI values of 3a were found as 4.51, 1.43 and 3.66 against A549, BT20 and SK-MEL 128 cell lines. The cell cycle arrest was investigated against A549 cells by flow cytometry and obtained results indicated that both compounds induce cell cycle arrest at G0/G1 phase. All of obtained results demonstrated that 3a had lead anticancer agent toward lung, breast and melanoma due to its high selectivity to cancer cell lines.
关键词： Water solubility,Cytotoxicity,Topoisomerases.,DNA,Phthalocyanine,Cell cycle arrest
更新于2025-09-19 17:15:36
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Cell cycle dynamics during diapause entry and exit in an annual killifish revealed by FUCCI technology
摘要： Background: Annual killifishes are adapted to surviving and reproducing over alternating dry and wet seasons. During the dry season, all adults die and desiccation-resistant embryos remain encased in dry mud for months or years in a state of diapause where their development is halted in anticipation of the months that have to elapse before their habitats are flooded again. Embryonic development of annual killifishes deviates from canonical teleost development. Epiblast cells disperse during epiboly, and a “dispersed phase” precedes gastrulation. In addition, annual fish have the ability to enter diapause and block embryonic development at the dispersed phase (diapause I), mid-somitogenesis (diapause II) and the final phase of development (diapause III). Developmental transitions associated with diapause entry and exit can be linked with cell cycle events. Here we set to image this transition in living embryos. Results: To visibly explore cell cycle dynamics during killifish development in depth, we created a stable transgenic line in Nothobranchius furzeri that expresses two fluorescent reporters, one for the G1 phase and one for the S/G2 phases of the cell cycle, respectively (Fluorescent Ubiquitination-based Cell Cycle Indicator, FUCCI). Using this tool, we observed that, during epiboly, epiblast cells progressively become quiescent and exit the cell cycle. All embryos transit through a phase where dispersed cells migrate, without showing any mitotic activity, possibly blocked in the G1 phase (diapause I). Thereafter, exit from diapause I is synchronous and cells enter directly into the S phase without transiting through G1. The developmental trajectories of embryos entering diapause and of those that continue to develop are different. In particular, embryos entering diapause have reduced growth along the medio-lateral axis. Finally, exit from diapause II is synchronous for all cells and is characterized by a burst of mitotic activity and growth along the medio-lateral axis such that, by the end of this phase, the morphology of the embryos is identical to that of direct-developing embryos. Conclusions: Our study reveals surprising levels of coordination of cellular dynamics during diapause and provides a reference framework for further developmental analyses of this remarkable developmental quiescent state.
关键词： Diapause,FUCCI technology,Cell cycle,Nothobranchius furzeri,Annual killifishes
更新于2025-09-11 14:15:04
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Radiology, Lasers, Nanoparticles and Prosthetics || 8. Cell cycle and cancer
摘要： The present chapter is intended to provide a basic understanding of the cell’s life cycle and the difference between normal and cancerous cells. This information is a prerequisite for the rationale behind cancer treatment plans using radiotherapy discussed in Chapters 9–12. For more specific and detailed information on cell cycle the reader is referred to standard biology [1] or physiology textbooks listed under “Further reading”. Here we focus the discussion on the relation between dose and cell survival rate that is contextual information for the following chapters on radiotherapy.
关键词： radiation response,biological effectiveness,cell cycle,DNA replication,mitosis,oncogenes,apoptosis,tumor suppressors,fractionation,hypoxia,chemotherapy,radiotherapy,cancer
更新于2025-09-11 14:15:04
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Concurrent live imaging of DNA double-strand break repair and cell-cycle progression by CRISPR/Cas9-mediated knock-in of a tricistronic vector
摘要： Cell-cycle progression can be arrested by ionizing radiation-induced DNA double-strand breaks (DSBs). Although DSBs are patched by DSB repair systems, which comprise proteins such as p53-binding protein 1 (53BP1), the relationship between DSB repair progression and cell-cycle status in living cells is unclear. The probe FUCCI (fluorescent ubiquitination-based cell-cycle indicator) was previously developed for visualizing cell-cycle status. Here, we established novel live-imaging probes based on custom-designed plasmids designated “Focicles” harboring a tricistronic compartment encoding distinct fluorescent proteins ligated to the murine 53BP1 foci-forming region (FFR) and two cell-cycle indicators that are known components of FUCCI (hCdt1 and hGmnn). We used CRISPR/Cas9-mediated genome editing to obtain Focicle knock-in cell lines in NIH3T3 cells, which were subject to X-ray irradiation that induced comparable numbers of Focicle and endogenous-53BP1 foci. In addition, the Focicle probes enabled the kinetic analysis of both DSB repair and cell-cycle arrest/progression after irradiation, demonstrating that the Focicle knock-in cells progressed to cell division after DNA damage elimination. These newly developed probes can help to gain a better understanding of the dynamics of DSB repair and cell-cycle control to in turn guide cancer treatment development and cancer-risk assessments.
关键词： FUCCI,CRISPR/Cas9,53BP1,DSB repair,live imaging,cell-cycle progression,DNA double-strand breaks
更新于2025-09-10 09:29:36
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Brahma deficiency in keratinocytes promotes UV carcinogenesis by accelerating the escape from cell cycle arrest and the formation of DNA photolesions
摘要： Background: Ultraviolet radiation (UVR) is the principal cause of keratinocyte skin cancers. Previous work found that levels of the chromatin remodelling protein, Brahma (Brm), are diminished during the progression from actinic keratoses to cutaneous squamous cell carcinomas in humans, and its loss in UV-irradiated mouse skin causes epidermal hyperplasia and increased tumour incidence. Methods: The skins of mice and mouse and human keratinocytes deficient in Brm were exposed to UVR and evaluated for cell cycle progression and DNA damage response. Objective: To identify the mechanisms by which loss of Brm contributes to UVR-induced skin carcinogenesis. Results: In both mouse keratinocytes and HaCaT cells, Brm deficiency led to an increased cell population growth following UVR exposure compared to cells with normal levels of Brm. Cell cycle analysis using a novel assay showed that Brm-deficient keratinocytes entered cell cycle arrest normally, but escaped from cell cycle arrest faster, enabling them to begin proliferating earlier. In mouse keratinocytes, Brm primarily affected accumulation in G0/G1-phase, whereas in HaCaT cells, which lack normal p53, accumulation in G2/M-phase was affected. Brm-deficient keratinocytes in mouse skin and human cell cultures also had higher levels of UVR-induced cyclobutane pyrimidine dimer photolesions. These effects occurred without any compensatory increase in DNA repair or cell death to remove photolesions or the cells that harbor them from the keratinocyte population. Conclusion: The loss of Brm in keratinocytes exposed to UVR enables them to resume proliferation while harboring DNA photolesions, leading to an increased fixation of mutations and, consequently, increased carcinogenesis.
关键词： SWI/SNF,Cutaneous squamous cell carcinoma,UV radiation,Cell cycle arrest,DNA damage
更新于2025-09-04 15:30:14
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Effect of Surface Coating of Gold Nanoparticles on Cytotoxicity and Cell Cycle Progression
摘要： Gold nanoparticles (GNPs) are usually wrapped with biocompatible polymers in biomedical field, however, the effect of biocompatible polymers of gold nanoparticles on cellular responses are still not fully understood. In this study, GNPs with/without polymer wrapping were used as model probes for the investigation of cytotoxicity and cell cycle progression. Our results show that the bovine serum albumin (BSA) coated GNPs (BSA-GNPs) had been transported into lysosomes after endocytosis. The lysosomal accumulation had then led to increased binding between kinesin 5 and microtubules, enhanced microtubule stabilization, and eventually induced G2/M arrest through the regulation of cadherin 1. In contrast, the bare GNPs experienced lysosomal escape, resulting in microtubule damage and G0/G1 arrest through the regulation of proliferating cell nuclear antigen. Overall, our findings showed that both naked and BSA wrapped gold nanoparticles had cytotoxicity, however, they affected cell proliferation via different pathways. This will greatly help us to regulate cell responses for different biomedical applications.
关键词： surface biocompatibility,microtubule,proteomics,nanoparticle location,cell cycle
更新于2025-09-04 15:30:14