morphology-based-distinction-between-healthy-pathological-cells

Morphology-Based Distinction Between Healthy and Pathological Cells Utilizing Fourier Transforms and Self-Organizing Maps

The appearance and the movements of immune cells are driven by their environment. As a reaction to a pathogen invasion, the immune cells are recruited to ...

a-two-step-pyrolysis-gas-chromatography-method-with-mass

A Two-Step Pyrolysis-Gas Chromatography Method with Mass Spectrometric Detection for Identification of Tattoo Ink Ingredients and Counterfeit Products

Tattoo inks are complex mixtures of ingredients. Each of them possesses different chemical properties which have to be addressed upon chemical analysis. ...

preparation-of-nanoparticles-for-tof-sims-and-xps-analysis

Preparation of Nanoparticles for ToF-SIMS and XPS Analysis

Nanoparticles have gained increasing attention in recent years due to their potential and application in different fields including medicine, cosmetics, ...

3d-printing-evaluating-particle-emissions-of-a-3d-printing-pen

3D Printing - Evaluating Particle Emissions of a 3D Printing Pen

Three-dimensional (3D) printing as a type of additive manufacturing shows continuing increase in application and consumer popularity. The fused filament ...

versatile-dual-inlet-sample-introduction-system-for-multi-mode-single

Versatile Dual-Inlet Sample Introduction System for Multi-Mode Single Particle Inductively Coupled Plasma Mass Spectrometry Analysis and Validation

Metal-containing nanoparticles (NP) can be characterized with inductively coupled plasma mass spectrometers (ICP-MS) in terms of their size and number ...

German Federal Institute for Risk Assessment (BfR)

Molecular, clinical and environmental toxicology. Preface.

Cancer is as a highly complex and multifactorial disease responsible for the death of hundreds of thousands of people in the western countries every year. Since cancer is clonal and due to changes at the level of the genetic material, viruses, chemical mutagens and other exogenous factors such as short-waved electromagnetic radiation that alter the structure of DNA are among the principal causes. The focus of this present review lies on the influence of the molecular structure of two well-investigated chemical carcinogens from the group of polycyclic aromatic hydrocarbons (PAHs), benzo[a]pyrene (BP) and dibenzo[a,l]pyrene (DBP). Although there is only one additional benzo ring present in the latter compound, DBP exerts much stronger genotoxic and carcinogenic effects in certain tumor models as compared to BP. Actually, DBP has been identified as the most potent tumorigen among all carcinogenic PAHs tested to date. The genotoxic effects of both compounds investigated in mammalian cells in culture or in animal models are described. Comparison of enzymatic activation, DNA binding levels of reactive diol-epoxide metabolites, efficiency of DNA adduct repair and mutagenicity provides some clues on why this compound is about 100-fold more potent in inducing tumors than BP. The data published during the past 20 years support and strengthen the idea that compound-inherent physicochemical parameters, along with inefficient repair of certain kinds of DNA lesions formed upon metabolic activation, can be considered as strong determinants for high carcinogenic potency of a chemical.

On the impact of the molecule structure in chemical carcinogenesis.

In physiology research, animal neurotoxins historically have served as valuable tools for identification, purification, and functional characterization of voltage-dependent ion channels. In particular, toxins from scorpions, sea anemones and cone snails were at the forefront of work aimed at illuminating the three-dimensional architecture of sodium channels. To date, at least six different receptor binding sites have been identified and--most of them--structurally assigned in terms of protein sequence and spatial disposition. Recent work on Australian funnel-web spiders identified certain peptidic ingredients as being responsible for the neurotoxicity of the crude venom. These peptides, termed delta-atracotoxins (delta-ACTX), consist of 42 amino acids and bind to voltage-gated sodium channels in the same way as classical scorpion alpha-toxins. According to the 'voltage-sensor trapping model' proposed in the literature, delta-ACTX isoforms interact with the voltage sensor S4 transmembrane segment of alpha-subunit domain IV, thereby preventing its normal outward movement and concurrent conformational changes required for inactivation of the channel. As consequence prolonged action potentials at autonomic or somatic synapses induce massive transmitter release, resulting in clinical correlates of neuroexcitation (e.g., muscle fasciculation, spasms, paresthesia, tachycardia, diaphoresis, etc.). On the other hand, the major neurotoxin isolated from black widow spiders, alpha-latrotoxin (alpha-LTX), represents a 132 kDa protein consisting of a unique N-terminal sequence and a C-terminal part harboring multiple ankyrin-like repeats. Upon binding to one of its specific presynaptic receptors, alpha-LTX has been shown to tetramerize under physiological conditions to form Ca2+-permeable pores in presynaptic membranes. The molecular model worked out during recent years separates two distinguishable receptor-mediated effects. According to current knowledge, binding of the N terminus of alpha-LTX at one of its specific receptors either triggers intracellular signaling cascades, resulting in phospholipase C-mediated mobilization of presynaptic Ca2+ stores, or leads to the formation of tetrameric pore complexes, allowing extracellular Ca2+ to enter the presynaptic terminal. Alpha-LTX-triggered exocytosis and fulminant transmitter release at autonomic synapses may then provoke a clinical syndrome referred to as 'latrodectism', characterized by local and incapacitating pain, diaphoresis, muscle fasciculation, tremor, anxiety, and so forth. The present review aims at providing a short introduction into some of the exciting molecular effects induced by neurotoxins isolated from black widow and funnel-web spiders.

Mechanistic insights on spider neurotoxins.

Increasing use of silver nanoparticles (Ag-NPs) in various products is resulting in a greater likelihood of human exposure to these materials. Nevertheless, little is still known about the influence of carbohydrates on the toxicity and cellular uptake of nanoparticles.

Carbohydrate functionalization of silver nanoparticles modulates cytotoxicity and cellular uptake.

Long perceived as a form of exotic self-expression in some social fringe groups, tattoos have left their maverick image behind and become mainstream, particularly for young people. Historically, tattoo-related health and safety regulations have focused on rules of hygiene and prevention of infections. Meanwhile, the increasing popularity of tattooing has led to the development of many new colours, allowing tattoos to be more spectacular than ever before. However, little is known about the toxicological risks of the ingredients used. For risk assessment, safe intradermal application of these pigments needs data for toxicity and biokinetics and increased knowledge about the removal of tattoos. Other concerns are the potential for phototoxicity, substance migration, and the possible metabolic conversion of tattoo ink ingredients into toxic substances. Similar considerations apply to cleavage products that are formed during laser-assisted tattoo removal. In this Review, we summarise the issues of concern, putting them into context, and provide perspectives for the assessment of the acute and chronic health effects associated with tattooing. 

A medical-toxicological view of tattooing.

Oxidative stress, a commonly used paradigm to explain nanoparticle (NP)-induced toxicity, results from an imbalance between reactive oxygen species (ROS) generation and detoxification. As one consequence, protein carbonyl levels may become enhanced. Thus, the qualitative and quantitative description of protein carbonylation may be used to characterize how biological systems respond to oxidative stress induced by NPs.

Proteomic analysis of protein carbonylation: a useful tool to unravel nanoparticle toxicity mechanisms.

At the dark end of the rainbow: data gaps in tattoo toxicology.

Despite our increasing understanding of molecular mechanisms controlling embryogenesis, the identification and characterization of teratogenic substances still heavily relies on animal testing. Embryonic development depends on cell-autonomous and non-autonomous processes including spatiotemporally regulated extracellular signaling activities. These have been elucidated in transgenic mouse models harboring easily detectable reporter genes under the control of evolutionarily conserved signaling cascades. We propose combining these transgenic mouse models and cells derived thereof with existing alternative toxicological testing strategies. This would enable the plausibility of in vitro data to be verified in light of in vivo data and, ultimately, facilitate regulatory acceptance of in vitro test methods.

Transgenic Mouse Models Transferred into the Test Tube: New Perspectives for Developmental Toxicity Testing In Vitro?

According to European legislation, tobacco additives may not increase the toxicity or the addictive potency of the product, but there is an ongoing debate on how to reliably characterize and measure such properties. Further, too little is known on pyrolysis patterns of tobacco additives to assume that no additional toxicological risks need to be suspected. An on-line pyrolysis technique was used and coupled to gas chromatography-mass spectrometry (GC/MS) to identify the pattern of chemical species formed upon thermal decomposition of 19 different tobacco additives like raw cane sugar, licorice or cocoa. To simulate the combustion of a cigarette it was necessary to perform pyrolysis at inert conditions as well as under oxygen supply. All individual additives were pyrolyzed under inert or oxidative conditions at 350, 700 and 1000°C, respectively, and the formation of different toxicants was monitored. We observed the generation of vinyl acrylate, fumaronitrile, methacrylic anhydride, isobutyric anhydride and 3-buten-2-ol exclusively during pyrolysis of tobacco additives. According to the literature, these toxicants so far remained undetectable in tobacco or tobacco smoke. Further, the formation of 20 selected polycyclic aromatic hydrocarbons (PAHs) with molecular weights of up to 278Da was monitored during pyrolysis of cocoa in a semi-quantitative approach. It was shown that the adding of cocoa to tobacco had no influence on the relative amounts of the PAHs formed.

Oxidative and inert pyrolysis on-line coupled to gas chromatography with mass spectrometric detection: On the pyrolysis products of tobacco additives.

Genotoxicity of nanomaterials in vitro: treasure or trash?

Nanosilver, due to its small particle size and enormous specific surface area, facilitates more rapid dissolution of ions than the equivalent bulk material; potentially leading to increased toxicity of nanosilver. This, coupled with their capacity to adsorb biomolecules and interact with biological receptors can mean that nanoparticles can reach sub-cellular locations leading to potentially higher localized concentrations of ions once those particles start to dissolve or degrade . Further complicating the story is the capacity for nanoparticles to generate reactive oxygen species, and to interact with, and potentially disturb the functioning of biomolecules such as proteins, enzymes and DNA. The fact that the nanoparticle size, shape, surface coating and a host of other factors contribute to these interactions, and that the particles themselves are evolving or ageing leads to further complications in terms of elucidating mechanisms of interaction and modes of action for silver nanoparticles, in contrast to dissolved silver species. This review aims to provide a critical assessment of the current understanding of silver nanoparticle toxicity, as well as to provide a set of pointers and guidelines for experimental design of future studies to assess the environmental and biological impacts of silver nanoparticles. In particular; in future we require a detailed description of the nanoparticles; their synthesis route and stabilisation mechanisms; their coating; and evolution and ageing under the exposure conditions of the assay. This would allow for comparison of data from different particles; different environmental or biological systems; and structure-activity or structure-property relationships to emerge as the basis for predictive toxicology. On the basis of currently available data; such comparisons or predictions are difficult; as the characterisation and time-resolved data is not available; and a full understanding of silver nanoparticle dissolution and ageing under different conditions is observed. Clear concerns are emerging regarding the overuse of nanosilver and the potential for bacterial resistance to develop. A significant conclusion includes the need for a risk-benefit analysis for all applications and eventually restrictions of the uses where a clear benefit cannot be demonstrated.

Mechanisms of Silver Nanoparticle Release, Transformation and Toxicity: A Critical Review of Current Knowledge and Recommendations for Future Studies and Applications.

The increasing prevalence of tattoos provoked safety concerns with respect to particle distribution and effects inside the human body. We used skin and lymphatic tissues from human corpses to address local biokinetics by means of synchrotron X-ray fluorescence (XRF) techniques at both the micro (μ) and nano (ν) scale. Additional advanced mass spectrometry-based methodology enabled to demonstrate simultaneous transport of organic pigments, heavy metals and titanium dioxide from skin to regional lymph nodes. Among these compounds, organic pigments displayed the broadest size range with smallest species preferentially reaching the lymph nodes. Using synchrotron μ-FTIR analysis we were also able to detect ultrastructural changes of the tissue adjacent to tattoo particles through altered amide I α-helix to β-sheet protein ratios and elevated lipid contents. Altogether we report strong evidence for both migration and long-term deposition of toxic elements and tattoo pigments as well as for conformational alterations of biomolecules that likely contribute to cutaneous inflammation and other adversities upon tattooing.

Synchrotron-based ν-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin.

Single cell imaging mass spectrometry opens up a complete new perspective for strategies in toxicological risk assessment and drug discovery. In particular, time-of-flight secondary ion mass spectrometry (ToF-SIMS) with its high spatial and depth resolution is becoming part of the imaging mass spectrometry toolbox used for single cell analysis. Recent instrumentation advancements in combination with newly developed cluster ion guns allow 3-dimensional reconstruction of single cells together with a spatially resolved compound location and quantification on nanoscale depth level. The exact location and quantification of a single compound or even of a set of compounds is no longer restricted to the two dimensional space within single cells, but is available for voxels, a cube-sized 3-dimensional space, rather than pixels. The information gathered from one voxel is further analysed using multivariate statistical methodology like maximum autocorrelation factors to co-locate the compounds of interest within intracellular organelles like nucleus, mitochondria or golgi apparatus. Furthermore, the cell membrane may be resolved, including adhering compounds and potential changes of the lipid patterns. The generated information can be used further for a first evaluation of intracellular target specifity of new drug candidates or for the toxicological risk assessment of environmental chemicals and their intracellular metabolites. Additionally, single cell lipidomics and metabolomics enable for the first time an in-depth understanding of the activation or inhibition of cellular biosynthesis and signalling pathways.

Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS): A New Tool for the Analysis of Toxicological Effects on Single Cell Level.

CMR substances in consumer products: from food contact materials to toys.

During the last few decades, nanotechnology has evolved into a success story, apparent from a steadily increasing number of scientific publications as well as a large number of applications based on engineered nanomaterials (ENMs). Its widespread uses suggest a high relevance for consumers, workers and the environment, hence justifying intensive investigations into ENM-related adverse effects as a prerequisite for nano-specific regulations. In particular, the inhalation of airborne ENMs, being assumed to represent the most hazardous type of human exposure to these kinds of particles, needs to be scrutinized. Due to an increased awareness of possible health effects, which have already been seen in the case of ultrafine particles (UFPs), research and regulatory measures have set in to identify and address toxic implications following their almost ubiquitous occurrence. Although ENM properties differ from those of the respective bulk materials, the available assessment protocols are often designed for the latter. Despite the large benefit ensuing from the application of nanotechnology, many issues related to ENM behavior and adverse effects are not fully understood or should be examined anew. The traditional hypothesis that ENMs exhibit different or additional hazards due to their "nano" size has been challenged in recent years and ENM categorization according to their properties and toxicity mechanisms has been proposed instead. This review summarizes the toxicological effects of inhaled ENMs identified to date, elucidating the modes of action which provoke different mechanisms in the respiratory tract and their resulting effects. By linking particular mechanisms and adverse effects to ENM properties, grouping of ENMs based on toxicity-related properties is supposed to facilitate toxicological risk assessment. As intensive studies are still required to identify these "ENM classes", the need for alternatives to animal studies is evident and advances in cell-based test systems for pulmonary research are presented here. We hope to encourage the ongoing discussion about ENM risks and to advocate the further development and practice of suitable testing and grouping methods.

The impact of nanomaterial characteristics on inhalation toxicity.

Tissue engineering technologies involving growth factors have produced one of the most advanced generations of diabetic wound healing solutions. Using this approach, a nanocomposite carrier was designed using Poly(d,l-lactide--glycolide) (PLGA)/Gelatin polymer solutions for the simultaneous release of recombinant human epidermal growth factor (rhEGF) and gentamicin sulfate at the wound site to hasten the process of diabetic wound healing and inactivation of bacterial growth. The physicochemical characterization of the fabricated scaffolds was carried out using scanning electron microscopy (SEM) and X-ay diffraction (XRD). The scaffolds were analyzed for thermal stability using thermogravimetric analysis and differential scanning calorimetry. The porosity, biodegradability, and swelling behavior of the scaffolds was also evaluated. Encapsulation efficiency, drug loading capacity, and in vitro drug release were also investigated. Further, the bacterial inhibition percentage and detailed in vivo biocompatibility for wound healing efficiency was performed on diabetic C57BL6 mice with dorsal wounds. The scaffolds exhibited excellent wound healing and continuous proliferation of cells for 12 days. These results support the applicability of such systems in rapid healing of diabetic wounds and ulcers.

ArticleTotal : 5	Year
Publication title	2018
Publication title	2019
Publication title	2020
Publication title	2020
Publication title	2020

Article	Year
Molecular, clinical and environmental toxicology. Preface. EXS\| PubMed ID: 19157055	2009
On the impact of the molecule structure in chemical carcinogenesis. EXS\| PubMed ID: 19157061	2009
Mechanistic insights on spider neurotoxins. EXS\| PubMed ID: 20358687	2010
Carbohydrate functionalization of silver nanoparticles modulates cytotoxicity and cellular uptake. Journal of nanobiotechnology\| PubMed ID: 25524171	2014
A medical-toxicological view of tattooing. Lancet (London, England)\| PubMed ID: 26211826	2016
Proteomic analysis of protein carbonylation: a useful tool to unravel nanoparticle toxicity mechanisms. Particle and fibre toxicology\| PubMed ID: 26525058	2015
At the dark end of the rainbow: data gaps in tattoo toxicology. Archives of toxicology\| PubMed ID: 27169852	2016
Transgenic Mouse Models Transferred into the Test Tube: New Perspectives for Developmental Toxicity Testing In Vitro? Trends in pharmacological sciences\| PubMed ID: 27450043	2016
Oxidative and inert pyrolysis on-line coupled to gas chromatography with mass spectrometric detection: On the pyrolysis products of tobacco additives. International journal of hygiene and environmental health\| PubMed ID: 27622657	2016
Genotoxicity of nanomaterials in vitro: treasure or trash? Archives of toxicology\| PubMed ID: 27743112	2016
Mechanisms of Silver Nanoparticle Release, Transformation and Toxicity: A Critical Review of Current Knowledge and Recommendations for Future Studies and Applications. Materials (Basel, Switzerland)\| PubMed ID: 28809275	2013
Synchrotron-based ν-XRF mapping and μ-FTIR microscopy enable to look into the fate and effects of tattoo pigments in human skin. Scientific reports\| PubMed ID: 28900193	2017
Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS): A New Tool for the Analysis of Toxicological Effects on Single Cell Level. Toxics\| PubMed ID: 29051411	2016
CMR substances in consumer products: from food contact materials to toys. Archives of toxicology\| PubMed ID: 29546521	2018
The impact of nanomaterial characteristics on inhalation toxicity. Toxicology research\| PubMed ID: 30090585	2018
In Vivo Biocompatibility of Electrospun Biodegradable Dual Carrier (Antibiotic + Growth Factor) in a Mouse Model-Implications for Rapid Wound Healing. Pharmaceutics\| PubMed ID: 31013995	2019
Tattooing: overriding the skin barrier and the journey into the unknown. Archives of toxicology\| PubMed ID: 31838564	2020

Andreas Luch

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