Abstract
In this paper we propose a theoretical model that predicts the oxidative stress potential of oxide nanoparticles by looking at the ability of these materials to perturb the intracellular ...redox state. The model uses reactivity descriptors to build the energy band structure of oxide nanoparticles, assuming a particle diameter larger than 20-30 nm and no surface states in the band gap, and predicts their ability to induce an oxidative stress by comparing the redox potentials of relevant intracellular reactions with the oxides' energy structure. Nanoparticles displaying band energy values comparable with redox potentials of antioxidants or radical formation reactions have the ability to cause an oxidative stress and a cytotoxic response in vitro. We discuss the model's predictions for six relevant oxide nanoparticles (TiO2, CuO, ZnO, FeO, Fe2O3, Fe3O4) with literature in vitro studies and calculate the energy structure for 64 additional oxide nanomaterials. Such a framework would guide the development of more rational and efficient screening strategies avoiding random or exhaustive testing of new nanomaterials.
Cancer is a key public health concern, being the second leading cause of worldwide morbidity and mortality after cardiovascular diseases. At the global level, cancer prevalence, incidence and ...mortality rates are increasing. These trends are not fully explained by a growing and ageing population: with marked regional and socioeconomic disparities, lifestyle factors, the resources dedicated to preventive medicine, and the occupational and environmental control of hazardous chemicals all playing a role. While it is difficult to establish the contribution of chemical exposure to the societal burden of cancer, a number of measures can be taken to better assess the carcinogenic properties of chemicals and manage their risks. This paper discusses how these measures can be informed not only by the traditional data streams of regulatory toxicology, but also by using new toxicological assessment methods, along with indicators of public health status based on biomonitoring. These diverse evidence streams have the potential to form the basis of an integrated and more effective approach to cancer prevention.
Opportunities for carcinogenicity assessment to address the challenges of cancer disease and chemicals in the environment. The safety assessment of carcinogenicity needs to evolve to keep pace with changes in the chemical environment and cancer epidemiology. Future strategies for assessing carcinogenicity based on a more holistic approach, can take into account the prevalence of certain cancers, the contribution to the disease of different risk factors, the study of relationships between chemical exposures and risk factors, the disease aetiology and links with other disorders. In addition, changes in chemical exposure patterns and exposed populations are also critical considerations. Display omitted
•Cancer has become a key public health concern worldwide and at EU level.•Cancer disease is a central priority of EU public health policy.•Public health policy actions cannot be decoupled from environmental policy actions.•Carcinogenicity assessment must evolve to ensure adequate levels of human protection.•The regulatory assessment of chemical toxicity should consider human specific cancers.
The failing human heart is characterized by metabolic abnormalities, but these defects remains incompletely understood. In animal models of heart failure there is a switch from a predominance of ...fatty acid utilization to the more oxygen-sparing carbohydrate metabolism. Recent studies have reported decreases in myocardial lipid content, but the inclusion of diabetic and nondiabetic patients obscures the distinction of adaptations to metabolic derangements from adaptations to heart failure per se.
We performed both unbiased and targeted myocardial lipid surveys using liquid chromatography-mass spectroscopy in nondiabetic, lean, predominantly nonischemic, advanced heart failure patients at the time of heart transplantation or left ventricular assist device implantation. We identified significantly decreased concentrations of the majority of myocardial lipid intermediates, including long-chain acylcarnitines, the primary subset of energetic lipid substrate for mitochondrial fatty acid oxidation. We report for the first time significantly reduced levels of intermediate and anaplerotic acyl-coenzyme A (CoA) species incorporated into the Krebs cycle, whereas the myocardial concentration of acetyl-CoA was significantly increased in end-stage heart failure. In contrast, we observed an increased abundance of ketogenic β-hydroxybutyryl-CoA, in association with increased myocardial utilization of β-hydroxybutyrate. We observed a significant increase in the expression of the gene encoding succinyl-CoA:3-oxoacid-CoA transferase, the rate-limiting enzyme for myocardial oxidation of β-hydroxybutyrate and acetoacetate.
These findings indicate increased ketone utilization in the severely failing human heart independent of diabetes mellitus, and they support the role of ketone bodies as an alternative fuel and myocardial ketone oxidation as a key metabolic adaptation in the failing human heart.
The body of EU chemicals legislation has evolved since the 1960s, producing the largest knowledge base on chemicals worldwide. Like any evolving system, however, it has become increasingly diverse ...and complex, resulting in inefficiencies and potential inconsistencies. In the light of the EU Chemicals Strategy for Sustainability, it is therefore timely and reasonable to consider how aspects of the system could be simplified and streamlined, without losing the hard-earned benefits to human health and the environment.
In this commentary, we propose a conceptual framework that could be the basis of Chemicals 2.0 – a future safety assessment and management approach that is based on the application of New Approach Methodologies (NAMs), mechanistic reasoning and cost-benefit considerations. Chemicals 2.0 is designed to be a more efficient and more effective approach for assessing chemicals, and to comply with the EU goal to completely replace animal testing, in line with Directive 2010/63/EU.
We propose five design criteria for Chemicals 2.0 to define what the future system should achieve. The approach is centered on a classification matrix in which NAMs for toxicodynamics and toxicokinetics are used to classify chemicals according to their level of concern. An important principle is the need to ensure an equivalent, or higher, protection level.
•There is a need to assess and manage chemicals more efficiently and effectively.•Chemicals 2.0 is a vision for a future safety assessment and management framework.•We propose five design criteria for Chemicals 2.0•NAM-based toxicodynamic and toxicokinetic data classify chemicals in concern levels.•A multi-stakeholder collaboration would develop the approach and build confidence.
In this chapter, we give a brief overview of the regulatory requirements for acute systemic toxicity information in the European Union, and we review structure-based computational models that are ...available and potentially useful in the assessment of acute systemic toxicity. Emphasis is placed on quantitative structure-activity relationship (QSAR) models implemented by means of a range of software tools. The most recently published literature models for acute systemic toxicity are also discussed, and perspectives for future developments in this field are offered.
This paper summarizes current challenges, the potential use of novel scientific methodologies, and ways forward in the risk assessment and risk management of mixtures. Generally, methodologies to ...address mixtures have been agreed; however, there are still several data and methodological gaps to be addressed. New approach methodologies can support the filling of knowledge gaps on the toxicity and mode(s) of action of individual chemicals. (Bio)Monitoring, modeling, and better data sharing will support the derivation of more realistic co-exposure scenarios. As knowledge and data gaps often hamper an in-depth assessment of specific chemical mixtures, the option of taking account of possible mixture effects in single substance risk assessments is briefly discussed. To allow risk managers to take informed decisions, transparent documentation of assumptions and related uncertainties is recommended indicating the potential impact on the assessment. Considering the large number of possible combinations of chemicals in mixtures, prioritization is needed, so that actions first address mixtures of highest concern and chemicals that drive the mixture risk. As chemicals with different applications and regulated separately might lead to similar toxicological effects, it is important to consider chemical mixtures across legislative sectors.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Histone acetylation plays important roles in gene regulation, DNA replication, and the response to DNA damage, and it is frequently deregulated in tumors. We postulated that tumor cell histone ...acetylation levels are determined in part by changes in acetyl coenzyme A (acetyl-CoA) availability mediated by oncogenic metabolic reprogramming. Here, we demonstrate that acetyl-CoA is dynamically regulated by glucose availability in cancer cells and that the ratio of acetyl-CoA:coenzyme A within the nucleus modulates global histone acetylation levels. In vivo, expression of oncogenic Kras or Akt stimulates histone acetylation changes that precede tumor development. Furthermore, we show that Akt’s effects on histone acetylation are mediated through the metabolic enzyme ATP-citrate lyase and that pAkt(Ser473) levels correlate significantly with histone acetylation marks in human gliomas and prostate tumors. The data implicate acetyl-CoA metabolism as a key determinant of histone acetylation levels in cancer cells.
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•Acetyl-CoA:CoA ratio is glucose sensitive and regulates histone acetylation levels•Oncogenic AKT expression promotes elevated histone acetylation in vitro and in vivo•ACLY phosphorylation by AKT enables sustained histone acetylation in low glucose•Histone acetylation and pAKT(Ser473) levels correlate significantly in human tumors
Lee et al. show that metabolic reprogramming induced by an oncogene affects histone acetylation. Under conditions of low glucose, Akt activates the acetyl-CoA-generating enzyme ATP-citrate lyase, leading to alterations in histone acetylation marks in tumors. In vivo, oncogenic Kras or Akt expression stimulates histone acetylation changes preceding tumor development.
The antitumor agent lonidamine (LND; 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid) is known to interfere with energy-yielding processes in cancer cells. However, the effect of LND on central ...energy metabolism has never been fully characterized. In this study, we report that a significant amount of succinate is accumulated in LND-treated cells. LND inhibits the formation of fumarate and malate and suppresses succinate-induced respiration of isolated mitochondria. Utilizing biochemical assays, we determined that LND inhibits the succinate-ubiquinone reductase activity of respiratory complex II without fully blocking succinate dehydrogenase activity. LND also induces cellular reactive oxygen species through complex II, which reduced the viability of the DB-1 melanoma cell line. The ability of LND to promote cell death was potentiated by its suppression of the pentose phosphate pathway, which resulted in inhibition of NADPH and glutathione generation. Using stable isotope tracers in combination with isotopologue analysis, we showed that LND increased glutaminolysis but decreased reductive carboxylation of glutamine-derived α-ketoglutarate. Our findings on the previously uncharacterized effects of LND may provide potential combinational therapeutic approaches for targeting cancer metabolism.
Macrophage activation/polarization to distinct functional states is critically supported by metabolic shifts. How polarizing signals coordinate metabolic and functional reprogramming, and the ...potential implications for control of macrophage activation, remains poorly understood. Here we show that IL-4 signaling co-opts the Akt-mTORC1 pathway to regulate Acly, a key enzyme in Ac-CoA synthesis, leading to increased histone acetylation and M2 gene induction. Only a subset of M2 genes is controlled in this way, including those regulating cellular proliferation and chemokine production. Moreover, metabolic signals impinge on the Akt-mTORC1 axis for such control of M2 activation. We propose that Akt-mTORC1 signaling calibrates metabolic state to energetically demanding aspects of M2 activation, which may define a new role for metabolism in supporting macrophage activation.
Currently, the identification of chemicals that have the potential to induce developmental neurotoxicity (DNT) is based on animal testing. Since at the regulatory level, systematic testing of DNT is ...not a standard requirement within the EU or USA chemical legislation safety assessment, DNT testing is only performed in higher tiered testing triggered based on chemical structure activity relationships or evidence of neurotoxicity in systemic acute or repeated dose toxicity studies. However, these triggers are rarely used and, in addition, do not always serve as reliable indicators of DNT, as they are generally based on observations in adult rodents. Therefore, there is a pressing need for developing alternative methodologies that can reliably support identification of DNT triggers, and more rapidly and cost-effectively support the identification and characterization of chemicals with DNT potential.
We propose to incorporate mechanistic knowledge and data derived from in vitro studies to support various regulatory applications including: (a) the identification of potential DNT triggers, (b) initial chemical screening and prioritization, (c) hazard identification and characterization, (d) chemical biological grouping, and (e) assessment of exposure to chemical mixtures. Ideally, currently available cellular neuronal/glial models derived from human induced pluripotent stem cells (hiPSCs) should be used as they allow evaluation of chemical impacts on key neurodevelopmental processes, by reproducing different windows of exposure during human brain development. A battery of DNT in vitro test methods derived from hiPSCs could generate valuable mechanistic data, speeding up the evaluation of thousands of compounds present in industrial, agricultural and consumer products that lack safety data on DNT potential.
•Current in vivo developmental neurotoxicity (DNT) testing is not efficient and coverage is sparse.•In vitro mechanistic data could support various regulatory applications.•Human induced pluripotent stem cell-derived neuronal models are recommended for DNT testing.•Further development of adverse outcome pathways relevant to DNT is urgently needed.•In vitro approaches should be included in regulatory DNT testing
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