An ancestral molecular response to nanomaterial particulates.

The varied transcriptomic response to nanoparticles has hampered the understanding of the mechanism of action. Here, by performing a meta-analysis of a large collection of transcriptomics data from various engineered nanoparticle exposure studies, we identify common patterns of gene regulation that impact the transcriptomic response. Analysis identifies deregulation of immune functions as a prominent response across different exposure studies. Looking at the promoter regions of these genes, a set of binding sites for zinc finger transcription factors C2H2, involved in cell stress responses, protein misfolding and chromatin remodelling and immunomodulation, is identified. The model can be used to explain the outcomes of mechanism of action and is observed across a range of species indicating this is a conserved part of the innate immune system.

Computational study of the effect of size and surface functionalization on Au nanoparticles on their stability to study biological descriptors.

The effects of varying nanoparticle size; polyethylene glycol (PEG) molecule length, type, and density; and functional groups for drug delivery systems are investigated computationally. A molecular dynamics (MD) study in the framework of a Monte Carlo simulated annealing scheme is done on gold nanoparticles (Au NPs) for sizes of 2.6 nm, 3.4 nm and 6.8 nm. The bonding of PEG molecules is investigated, and the binding energy (BE) is analysed as a reference to chemisorption and physisorption of the molecules. To investigate the frontier molecular orbitals and molecular electrostatic potentials, density functional theory (DFT) simulations are also performed for various PEG lengths and functional groups (FGs). The study reports on three conclusions: firstly, reducing the Au NP size leads to coordination number (CN) loss as the number of lowly coordinated atoms increases with decreasing particle size. Secondly, the stability of the Au-PEG system is independent of length beyond [Formula: see text]. And due to PEG high steric repulsion, the number of these molecules that can be physically adsorbed to the surface is limited. And thirdly, the FGs can be grouped into electron-withdrawing group (-NTA, Biotin, COOH) and electron-donating group (-NH2, OH). In future work, we will study how these conclusions influence the Au drug delivery system toxicity and cellular uptake.

Recent developments in computational and experimental studies of physicochemical properties of Au and Ag nanostructures on cellular uptake and nanostructure toxicity.

Recent developments in studies of the uptake and toxicity of both gold (Au) and silver (Ag) nanostructures (NS) in drug delivery systems have shown that physicochemical properties play an important role. Physicochemical properties of engineered NS such as size, shape, coordination chemistry, surface charge, and surface chemistry generally manifest in reactivity, surface energetics and electronic properties of the nanomaterials. This review discusses the computational and experimental studies conducted to study the effects of physicochemical properties on cellular uptake and nanostructure toxicity. The studies show that properties like coordination chemistry have often been overlooked when studying the high surface energy of NS.

In vitro toxicity and internalization of gold nanoparticles (AuNPs) in human epithelial colorectal adenocarcinoma (Caco-2) cells and the human skin keratinocyte (HaCaT) cells.

Ingestion and transdermal delivery are two common routes of nanoparticle (NP) exposure. In this study, the intracellular uptake, cytotoxicity and genotoxicity of 14 nm and 20 nm citrate-stabilized gold nanoparticles (AuNPs), 14 nm polyethylene glycol (PEG)-liganded carboxyl AuNPs, 14 nm PEG-liganded hydroxyl AuNPs and 14 nm PEG-liganded amine AuNPs were assessed on human epithelial colorectal adenocarcinoma (Caco-2) cells and the human skin keratinocyte (HaCaT) cells. The uptake of AuNPs in the cells was confirmed through darkfield microscopy and hyperspectral imaging followed by spectral angle mapping (SAM). A high level of citrate AuNPs was found in both cell lines whilst uptake of PEGylated AuNPs was low, irrespective of their functional groups. Cytotoxicity assessed by cell impedance was only observed for the 14 nm citrate-stabilized AuNPs. Enhanced cell proliferation was also observed in 14 nm PEG-liganded hydroxyl and 14 nm PEG-liganded amine AuNP-treated Caco-2 and HaCaT cells. For the assessment of genotoxicity, the in vitro micronucleus assay was used. Dose-dependent genotoxicity was observed in both Caco-2 and HaCaT cells, with all the AuNPs inducing genotoxicity. In conclusion, the entry of NPs into the cells as well as toxicity was dependent on their physicochemical properties such as surface coating and different chemical functional groups.

The ability of Warburgia salutaris extracts to protect against crystalline silica-induced cell injury.

In Southern Africa, the medicinal plant Warburgia salutaris is commonly used for the treatment of inflammatory and other diseases. The methanol extracts of W. salutaris were investigated with regard to a) production of proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma; b) activation of the transcription factor nuclear factor kappa B; and c) induction of deoxyribonucleic acid (DNA) damage and lipid peroxidation in the presence of crystalline silica particles. Due to its antioxidant properties, extracts of W. salutaris showed protective effects against crystalline silica-induced inflammatory cytokine expression, activation of nuclear transcription factor-kappaB, DNA strand breakage, and lipid peroxidation. Hence, W. salutaris may be a potential therapeutic agent against the fibrogenic and carcinogenic effects of crystalline silica.

Mechanistically identified suitable biomarkers of exposure, effect, and susceptibility for silicosis and coal-worker's pneumoconiosis: a comprehensive review.

Clinical detection of silicosis is currently dependent on radiological and lung function abnormalities, both late manifestations of disease. Markers of prediction and early detection of pneumoconiosis are imperative for the implementation of timely intervention strategies. Understanding the underlying mechanisms of the etiology of coal workers pneumoconiosis (CWP) and silicosis was essential in proposing numerous biomarkers that have been evaluated to assess effects following exposure to crystalline silica and/or coal mine dust. Human validation studies have substantiated some of these proposed biomarkers and argued in favor of their use as biomarkers for crystalline silica- and CWP-induced pneumoconiosis. A number of "ideal" biological markers of effect were identified, namely, Clara cell protein-16 (CC16) (serum), tumor necrosis factor-alpha (TNF-alpha) (monocyte release), interleukin-8 (IL-8) (monocyte release), reactive oxygen species (ROS) measurement by chemiluminescence (neutrophil release), 8-isoprostanes (serum), total antioxidant levels measured by total equivalent antioxidant capacity (TEAC), glutathione, glutathione peroxidase activity, glutathione S-transferase activity, and platelet-derived growth factor (PDGF) (serum). TNF-alpha polymorphism (blood cellular DNA) was identified as a biomarker of susceptibility. Further studies are planned to test the validity and feasibility of these biomarkers to detect either high exposure to crystalline silica and early silicosis or susceptibility to silicosis in gold miners in South Africa.

Studies on antibacterial, anti-inflammatory and antioxidant activity of herbal remedies used in the treatment of benign prostatic hyperplasia and prostatitis.

Crude water and ethanolic extracts of five herbal remedies reported in the literature for traditional treatment of benign prostatic hyperplasia (BPH) and/or prostatitis were investigated for their effect on hydroxyl scavenging activity, antibacterial activity and their ability to inhibit cyclooxygenase-1 and -2 (COX-1 and COX-2) catalysed prostaglandin biosynthesis. Both the water and ethanol extracts of Hypoxis hemerocallidea and Epilobium parviflorum inhibited the growth of Escherichia coli. All 10 extracts scavenged the hydroxyl radical but with various potencies (32-93%). Ethanolic extracts were the most active in inhibiting COX-1 catalysed prostaglandin biosynthesis. The ethanolic extract of Epilobium parviflorum showed inhibitory effects on both the COX-1 and -2 catalysed prostaglandin biosynthesis, inhibited growth of Escherichia coli and exerted antioxidant activity. Although these results support the traditional use of Epilobium parviflorum for treatment of prostatitis and BPH, further investigation is required, for this promising plant.

Influence of serum and amino acids on the accumulation of aminoisobutyrate by rat hepatoma cells. A dedifferentiation of transport routes?

Rat hepatoma cells accumulate considerably less 2-aminoisobutyrate after cultivating in the absence of serum--the change in rate of aminoisobutyrate uptake takes place within 1 h of serum starvation. Starvation of amino acids by contrast raises aminoisobutyrate uptake in the presence or absence of serum, but the cells are much less responsive to amino acid supply than to availability of serum. Phosphate (10 mM) reduced aminoisobutyrate uptake by cells grown in serum to that exhibited by serum-starved cells. Aminoisobutyrate uptake by cells grown in serum was reduced by glycine, proline, alanine, serine, glutamine, methylaminoisobutyrate and 2-aminonorbornane-2-carboxylate, the effects of methylaminoisobutyrate and 2-aminonorbornane-2-carboxylate being additive. However, similar inhibition phenomena were not seen for cells deprived of serum where aminoisobutyrate uptake tended to a relatively constant level insensitive to inhibitory influences, yet substantially greater than that arising by simple diffusion. The comparative insensitivity of our hepatoma line when starved of serum to competition and repression phenomena is in contrast to findings of others. Our results also suggest a lack of clear delineation of specificities for the A and L transport systems as usually defined.

Hazards identified and the need for health risk assessment in the South African mining industry.

Although mining plays a prominent role in the economy of South Africa, it is associated with many chemical hazards. Exposure to dust from mining can lead to many pathological effects depending on mineralogical composition, size, shape and levels and duration of exposure. Mining and processing of minerals also result in occupational exposure to toxic substances such as platinum, chromium, vanadium, manganese, mercury, cyanide and diesel particulate. South Africa has set occupational exposure limits (OELs) for some hazards, but mine workers are still at a risk. Since the hazard posed by a mineral depends on its physiochemical properties, it is recommended that South Africa should not simply adopt OELs from other countries but rather set her own standards based on local toxicity studies. The limits should take into account the issue of mixtures to which workers could be exposed as well as the health status of the workers. The mining industry is also a source of contamination of the environment, due inter alia to the large areas of tailings dams and dumps left behind. Therefore, there is need to develop guidelines for safe land-uses of contaminated lands after mine closure.

Can microwave radiation at high temperatures reduce the toxicity of fibrous crocidolite asbestos?

Exposure of animals and humans to crocidolite asbestos fibers produces fibrosis and two types of cancers: bronchogenic carcinoma and mesothelioma. It is therefore desirable to reduce toxicity of these fibers without affecting their other characteristics. In this study, commercial crocidolite asbestos fibers were radiated with microwave radiation at different temperatures. Radiated fibers and nonradiated original fibers were then studied by Mössbauer spectroscopy to quantify the amount of ferric and ferrous ions present at structurally different sites in each crocidolite sample. They were also studied for their ability to initiate the peroxidation of linoleic acid to assess the effect of radiation on this process. Results showed that microwave radiation reduced the total Fe2+/Fe3+ ratio. This reduction produced a concomitant decrease in the ability of the radiated samples to peroxidize linoleic acid.

The ability of mineral dusts and fibres to initiate lipid peroxidation. Part II: relationship to different particle-induced pathological effects.

Exposure to pathogenic mineral dusts and fibres is associated with pulmonary changes including fibrosis and cancer. Investigations into aetiological mechanisms of these diseases have identified modifications in specific macromolecules as well as changes in certain early processes, which have preceded fibrosis and cancer. Peroxidation of lipids is one such modification, which is observed following exposure to mineral dusts and fibres. Their ability to initiate lipid peroxidation and the parameters that determine this ability have recently been reviewed. Part II of this review examines the relationship between the capacity of mineral dusts and fibres to initiate lipid peroxidation and a number of pathological changes they produce. The oxidative modification of polyunsaturated fatty acids is a major contributor to membrane damage in cells and has been implicated in a great variety of pathological processes. In most pathological conditions where an induction of lipid peroxidation is observed it is assumed to be the consequence of disease, without further establishing if the induction of lipid peroxidation may have preceded or accompanied the disease. In the great majority of instances, however, despite the difficulty in proving this association, a causal relationship between lipid peroxidation and disease cannot be ruled out.

Hydroxyl radical production in the presence of fibres by a Fenton-type reaction.

Glass fibres are considered to be inert and therefore thought to present no real hazard to the health of people who inhale them. Results in the present study however indicate that these fibres are able to produce hydroxyl radicals in the presence of hydrogen peroxide by a Fenton-type reaction. Since hydroxyl radical is implicated in lipid peroxidation, single-strand DNA breaks and carcinogenesis, care should be exercised when dealing with glass fibres.

Lipid peroxidation in microsomes induced by crocidolite fibres.

When rat liver and lung microsomes were incubated with crocidolite fibres, a substantial increase in lipid peroxidation was observed. Increasing concentrations of this fibre in the incubation mixture, produced a concomitant induction in microsomal lipid peroxidation. This increase was very rapid as the reaction was almost complete within 10 min. The ability of these fibres to induce this process after a short period of incubation seems to be due to their binding to the microsomes. The iron present in the structure of crocidolite is thought to be responsible for catalysing the peroxidation. The formation of free radicals by asbestos and possible pathological sequelae are discussed.

Pharmacopoeia of traditional medicine in Venda.

Many researchers in different parts of the world are actively involved in recording the available information on traditional medicine. To contribute to this vast task, we chose Venda, one of the more remote tribes in Southern Africa. We found traditional healing to be very much alive and functioning in this area. Within 2 years of research, we could tabulate 151 medicinal plants with their galenics. Many of the plants listed were frequently used by different healers to treat the same ailment which might substantiate their reliability. On the other hand, certain plants were employed for various indications. Moreover, although the toxic effects of some plants are not included in our list, they are encountered by the Western medical doctors. Therefore, the benefits of compiling such lists on medicinal uses of different plants are twofold. To gain from the positive aspects of the traditional medicine and to eradicate, if possible, the harmful effects of some plants used by the traditional healers. However, during our study, it became clear that the plants used were with some exceptions mainly found in the vicinity of the habitat of the healer or the herbalist. It would therefore be useless to compile a more general pharmacopoeia for the African traditional healing as many of the useful plants in one area cannot be found in another. Hence, a more specific pharmacopoeia for each area would be necessary.

Evaluation of a new chelating agent for cadmium: a preliminary report.

The Plasma Mobilizing Index parameters of the newly synthesized chelating agent THP-12-ane N4, determined by computer simulation studies, have indicated that this chelating agent might be a good antagonist for cadmium intoxication. Experiments conducted on rats confirmed this observation and showed that THP-12-ane N4 might have the ability to chelate and mobilize cadmium in vivo.

In vitro effect of N-acetylcysteine on hepatocyte injury caused by dichlorodiphenyltrichloroethane and its metabolites.

The organochlorine pesticide, dichlorodiphenyltrichloroethane (DDT), is still used to combat the spread of malaria in several developing countries despite its accumulation and known hepatotoxic effects that have been demonstrated both in vitro and in vivo. N-Acetylcysteine (NAC) is a recognized hepatoprotective agent that has been reported to reduce hepatotoxicity initiated by many different compounds. The aim of this study was to determine whether NAC could counter in vitro hepatocyte injury induced by DDT or its two major metabolites, dichlorodiphenyldichloroethylene and dichlorodiphenyldichloroethane. HepG2 cell cultures were used to assess the following parameters of toxicity: cellular viability, intracellular levels of reactive oxygen species (ROS), mitochondrial membrane potential and initiation of apoptosis. None of the three test compounds induced ROS generation, yet exposure to any of the three compounds produced mitochondrial hyperpolarization, which was countered by NAC pretreatment. All three test compounds also induced apoptotic cell death, which was inhibited by NAC. Despite NAC counteracting some adverse intracellular changes due to organochlorine exposure, it appeared to aggravate the cytotoxic effects of the organochlorine compounds at low test concentrations. As the same outcome may also occur in vivo, results from the present study raise concern about the use of NAC as treatment for DDT-induced hepatotoxicity.

An update on the detoxification processes for silica particles and asbestos fibers: successess and limitations.

Inhalation of asbestos fibers and crystalline silica produces a number of diseases including fibrosis and cancer. Investigations into the mechanisms involved in mineral particle-induced toxicity indicated the importance of their surfaces in the pathological consequences. Masking of the surface sites has therefore featured prominently in a number of detoxification processes that have been investigated. The majority of the detoxification processes were, however, conducted to elucidate the involvement of a particular surface site in the toxicity of a specific mineral. Others were investigated with the aim of large industrial applications to be applied during mining, handling, processing, transporting, and disposing of minerals. It can be concluded that, to date, there is no single detoxification process that could be applied universally to all different types of mineral particles. Those that have shown some success could not completely abolish all adverse effects. Further elucidation of mechanisms of particle-induced toxicity may open new possibilities for detoxification processes.