Perception, Planning, and Scoping, Problem Formulation, and Hazard Identification
Ted W. Simon in Environmental Risk Assessment, 2019
Understanding and interpreting the results of in vitro assays is not easy, and in 2019, is still a work in progress. For example, many chemicals tested in the suite of ToxCast™ assays showed activation of a large number of assays over a narrow concentration range at which cytotoxicity is also observed. Essentially, cytotoxicity is a non-specific response indicating general disruption of cellular processes, whereas the specific responses often occurred at lower concentrations and observed responses were due to alterations in specific cellular targets. Hence, scientists at EPA’s National Center for Computational Toxicology explored this issue in detail and developed computational tools to distinguish specific from non-specific responses.162
Disruption of Cellular Growth Control and Signal Transduction Mechanisms as a Target for Cancer Chemotherapy
Robert I. Glazer in Developments in Cancer Chemotherapy, 2019
The major objective of cancer chemotherapy has been to poison cells with cytotoxic chemicals. There now exist many types of agents, treatments, and conditions that can injure or kill cancer cells, and an enormous amount of research effort has been invested in determining the underlying mechanisms of cytotoxicity. If one considers a cell as a collection of organelles and molecular assemblies, it seems reasonable that any of these targets could be susceptible to attack by cytotoxic agents. To some extent, this prediction has proven true — all aspects of cellular metabolism and physiology have known poisons and inhibitors. What is incomplete in the picture, however, is a link between the knowledge of a biochemical target for a drug and a molecular explanation of why a cell dies when this target is disrupted. If dihydrofolate reductase is inhibited, for example, is this inhibtion of an important enzyme itself responsible for cell death, or does the lack of products of the enzyme have additional metabolic repercussions that are the key event in cell death? Considering another locus for cytotoxicity, does physical breakage of DNA damage the ability of a cell to reproduce, or does DNA damage couple to other cellular regulatory mechanisms which are the central lethal events following exposure to DNA-damaging drugs? A related problem can also be stated: is DNA or enzyme damage the cause or the consequence of cytotoxicity?
Imaging of Cell Trafficking and Cell Tissue Homing
George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos in Handbook of Small Animal Imaging, 2018
Iron oxide nanoparticles for magnetic resonance imaging contain iron and, although it is a natural and essential mineral, an overdose can be toxic to cells (Soenen et al. 2011). Moreover, aggregation of these nanoparticles in the presence of a magnetic field can lead to embolization (Gupta et al. 2007). Several studies have looked into the adverse effects of iron oxide particles on cells, but the reports have been contradictory. Importantly, however, the variety of the applied methods and model systems to assess cytotoxicity plays a critical role and can contribute significantly to these contradictory findings (Soenen and De Cuyper 2010). As a result, many highlighted the need for a more standardized procedure for the assessment of nanoparticle cytotoxicity. In general, the toxicity associated with iron oxide nanoparticles, or their coatings, appears to be closely related to the release of ions and the generation of free radicals following passage through the cell’s lysosomes (Soenen and De Cuyper 2010; Taylor et al. 2012). On the positive side, the uptake and toxicity of these nanoparticles can be manipulated by modifications in the surface chemistry and selecting the right size and biocompatible coating of the nanomaterial (Alkilany and Murphy 2010).
Evolution of immunotherapy in the treatment of non-muscle-invasive bladder cancer
Published in Expert Review of Anticancer Therapy, 2022
Niyati Lobo, Alberto Martini, Ashish M. Kamat
A pivotal moment in cancer immunotherapy was the discovery that T-cell immune responses are regulated via on and off switches. These so-called ‘immune checkpoints’ shield the body against harmful immune responses and the induction of auto-immunity [46]. The interaction between CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) was found to be the ‘master switch’ for T-cell activation and, in subsequent years, several other immune checkpoints were identified, including programmed cell death protein 1–programmed cell death 1 ligand 1 (PD1–PDL1) [47,48]. During normal cellular function, programmed cell death-1 (PD-1) receptor is expressed on T-cells following T-cell receptor stimulation. Engagement of this receptor by its ligand, PD-L1, leads to T-cell neutralization, exhaustion, and reduced cytokine production [49]. As a result, T-cell-mediated cytotoxicity is inhibited. In the absence of PD-1 activation, immune effector cells, such as CD8 cytotoxic T-cells, will lead to target cell death following T-cell receptor activation. By over-expressing PD-L1, tumor cells are able to evade immune surveillance and subsequent destruction. Checkpoint inhibitors, therefore, function by blocking the binding of PD-1 with PD-L1, thus enabling cytotoxic T-cell activation against tumor cells.
New Multi-Walled carbon nanotube of industrial interest induce cell death in murine fibroblast cells
Published in Toxicology Mechanisms and Methods, 2021
Krissia Franco de Godoy, Joice Margareth de Almeida Rodolpho, Patricia Brassolatti, Bruna Dias de Lima Fragelli, Cynthia Aparecida de Castro, Marcelo Assis, Juliana Cancino Bernardi, Ricardo de Oliveira Correia, Yulli Roxenne Albuquerque, Carlos Speglich, Elson Longo, Fernanda de Freitas Anibal
In turn, cytotoxicity is related to the interaction of CNTs in the cellular environment, which in this case occurs in different ways (endocytosis, phagocytosis or needle-shaped penetration), which can trigger changes in cell cycle signaling and regulation (Aschberger et al. 2010; Firme and Bandaru 2010). The penetration of CNTs through the cell lipid bilayer membrane induces oxidative stress, free radical production, damage to proteins, impairment of genetic material and inflammation (Clichici et al. 2012; Mohanta et al. 2019; Prajapati et al. 2020). In addition, from a physicochemical point of view, this cytotoxicity is directly influenced by the type of nanoparticle, size, composition, surface charge, morphology, porosity, aggregation and solubility (Holsapple et al. 2005; Khan et al. 2019).
Evaluation of in vitro and in vivo genotoxic and antigenotoxic effects of Rhus coriaria
Published in Drug and Chemical Toxicology, 2021
Taygun Timocin, Mehmet Arslan, Hasan Basri Ila
When all our results are evaluated together, we conclude that RC is not genotoxic in vivo or in vitro. On the other hand, RC had an antigenotoxic effect at the highest concentration in vivo. The cytotoxic effect obtained in vitro was disappeared in vivo conditions. The highest concentration of RCE (2000 mg/kg) prevented a urethane-induced cytotoxic effect, and thus, a genotoxic effect in bone marrow cells. Cancer drugs (Wang et al.1998, Sung and Shuler 2009) and antimutagenic substances (Horn and Vargas 2003) often show their effects through cytotoxicity. In our study, the antigenotoxic effect in in vivo conditions occurred without cytotoxic effect. These results reveal the importance of this study and the fact that this plant should be investigated with different genotoxicity/mutagenicity test systems.