Effect Of Nanoparticles On The Biochemical And Behavioral Aging Phenotype Of The Nematode Caenorhabditis Elegans

Invertebrate animal models such as the nematode Caenorhabditis elegans (C. elegans) are increasingly used in nanotechnological applications. Research in this area covers a wide range from remote control of worm behavior by nanoparticles (NPs) to evaluation of organismal nanomaterial safety. Despite of the broad spectrum of investigated NP-bio interactions, little is known about the role of nanomaterials with respect to aging processes in C. elegans. We trace NPs in single cells of adult C. elegans and correlate particle distribution with the worm\u27s metabolism and organ function. By confocal microscopy analysis of fluorescently labeled NPs in living worms, we identify two entry portals for the uptake of nanomaterials via the pharynx to the intestinal system and via the vulva to the reproductive system. NPs are localized throughout the cytoplasm and the cell nucleus in single intestinal, and vulval B and D cells. Silica NPs induce an untimely accumulation of insoluble ubiquitinated proteins, nuclear amyloid and reduction of pharyngeal pumping that taken together constitute a premature aging phenotype of C. elegans on the molecular and behavioral level, respectively. Screening of different nanomaterials for their effects on protein solubility shows that polystyrene or silver NPs do not induce accumulation of ubiquitinated proteins suggesting that alteration of protein homeostasis is a unique property of silica NPs. The nematode C. elegans represents an excellent model to investigate the effect of different types of nanomaterials on aging at the molecule, cell, and whole organism level. © 2013 American Chemical Society

Localization of proteasomes and proteasomal proteolysis in the mammalian interphase cell nucleus by systematic application of immunocytochemistry

Proteasomes are ATP-driven, multisubunit proteolytic machines that degrade endogenous proteins into peptides and play a crucial role in cellular events such as the cell cycle, signal transduction, maintenance of proper protein folding and gene expression. Recent evidence indicates that the ubiquitin-proteasome system is an active component of the cell nucleus. A characteristic feature of the nucleus is its organization into distinct domains that have a unique composition of macromolecules and dynamically form as a response to the requirements of nuclear function. Here, we show by systematic application of different immunocytochemical procedures and comparison with signature proteins of nuclear domains that during interphase endogenous proteasomes are localized diffusely throughout the nucleoplasm, in speckles, in nuclear bodies, and in nucleoplasmic foci. Proteasomes do not occur in the nuclear envelope region or the nucleolus, unless nucleoplasmic invaginations expand into this nuclear body. Confirmedly, proteasomal proteolysis is detected in nucleoplasmic foci, but is absent from the nuclear envelope or nucleolus. The results underpin the idea that the ubiquitin-proteasome system is not only located, but also proteolytically active in distinct nuclear domains and thus may be directly involved in gene expression, and nuclear quality control. © 2007 Springer-Verlag

Pollutants Corrupt Resilience Pathways of Aging in the Nematode C. Elegans

Delaying aging while prolonging health and lifespan is a major goal in aging research. One promising strategy is to focus on reducing negative interventions such as pollution and their accelerating effect on age-related degeneration and disease. Here, we used the short-lived model organism C. elegans to analyze whether two candidate pollutants corrupt general aging pathways. We show that the emergent pollutant silica nanoparticles (NPs) and the classic xenobiotic inorganic mercury reduce lifespan and cause a premature protein aggregation phenotype. Comparative mass spectrometry revealed that increased insolubility of proteins with important functions in proteostasis is a shared phenotype of intrinsic- and pollution-induced aging supporting the hypothesis that proteostasis is a central resilience pathway controlling lifespan and aging. The presented data demonstrate that pollutants corrupt intrinsic aging pathways. Reducing pollution is, therefore, an important step to increasing healthy aging and prolonging life expectancies on a population level in humans and animals

Casein Α S1 Is Expressed By Human Monocytes And Upregulates The Production Of GM-CSF Via P38 MAPK

Caseins are major constituents of mammalian milks that are thought to be exclusively expressed in mammary glands and to function primarily as a protein source, as well as to ameliorate intestinal calcium uptake. In addition, proinflammatory and immunomodulatory properties have been reported for bovine caseins. Our aim was to investigate whether human casein α s1 (CSN1S1) is expressed outside the mammary gland and possesses immunomodulatory functions in humans as well. For this purpose, CSN1S1 mRNA was detected in primary human monocytes and CD4+ and CD8+ T cells, but not in CD19 + B cells. CSN1S1 protein was traceable in supernatants of cultured primary human CD14+ monocytes by ELISA. Similarly, CSN1S1 mRNA and protein were detected in the human monocytic cell lines HL60, U937, and THP1 but not in Mono Mac 6 cells. Moreover, permeabilized human monocytes and HL60 cells could be stained by immunofluorescence, indicating intracellular expression. Recombinant human CSN1S1 was bound to the surface of Mono Mac 6 cells and upregulated the expression of GM-CSF mRNA in primary human monocytes and Mono Mac 6 cells in a time- and concentration-dependent manner. A similar increase in GM-CSF protein was found in the culture supernatants. CSN1S1-dependent upregulation of GM-CSF was specifically blocked by the addition of the p38 MAPK inhibitor ML3403. Our results indicated that human CSN1S1 may possess an immunomodulatory role beyond its nutritional function in milk. It is expressed in human monocytes and stimulates the expression of the proinflammatory cytokine GM-CSF. Copyright © 2010 by The American Association of Immunologists, Inc

In Caenorhabditis elegans Nanoparticle-Bio-Interactions Become Transparent: Silica-Nanoparticles Induce Reproductive Senescence

While expectations and applications of nanotechnologies grow exponentially, little is known about interactions of engineered nanoparticles with multicellular organisms. Here we propose the transparent roundworm Caenorhabditis elegans as a simple but anatomically and biologically well defined animal model that allows for whole organism analyses of nanoparticle-bio-interactions. Microscopic techniques showed that fluorescently labelled nanoparticles are efficiently taken up by the worms during feeding, and translocate to primary organs such as epithelial cells of the intestine, as well as secondary organs belonging to the reproductive tract. The life span of nanoparticle-fed Caenorhabditis elegans remained unchanged, whereas a reduction of progeny production was observed in silica-nanoparticle exposed worms versus untreated controls. This reduction was accompanied by a significant increase of the ‘bag of worms’ phenotype that is characterized by failed egg-laying and usually occurs in aged wild type worms. Experimental exclusion of developmental defects suggests that silica-nanoparticles induce an age-related degeneration of reproductive organs, and thus set a research platform for both, detailed elucidation of molecular mechanisms and high throughput screening of different nanomaterials by analyses of progeny production

Exposome, Molecular Pathways and One Health: The Invertebrate <i>Caenorhabditis elegans</i>

Due to its preferred habitats in the environment, the free-living nematode Caenorhabditis elegans has become a realistic target organism for pollutants, including manufactured nanoparticles. In the laboratory, the invertebrate animal model represents a cost-effective tool to investigate the molecular mechanisms of the biological response to nanomaterials. With an estimated number of 22,000 coding genes and short life span of 2–3 weeks, the small worm is a giant when it comes to characterization of molecular pathways, long-term low dose pollutant effects and vulnerable age-groups. Here, we review (i) flows of manufactured nanomaterials and exposition of C. elegans in the environment, (ii) the track record of C. elegans in biomedical research, and (iii) its potential to contribute to the investigation of the exposome and bridge nanotoxicology between higher organisms, including humans. The role of C. elegans in the one health concept is taken one step further by proposing methods to sample wild nematodes and their molecular characterization by single worm proteomics

Effects of Airborne Nanoparticles on the Nervous System: Amyloid Protein Aggregation, Neurodegeneration and Neurodegenerative Diseases

How the environment contributes to neurodegenerative diseases such as Alzheimer&rsquo;s is not well understood. In recent years, science has found augmenting evidence that nano-sized particles generated by transport (e.g., fuel combustion, tire wear and brake wear) may promote Alzheimer&rsquo;s disease (AD). Individuals residing close to busy roads are at higher risk of developing AD, and nanomaterials that are specifically generated by traffic-related processes have been detected in human brains. Since AD represents a neurodegenerative disease characterized by amyloid protein aggregation, this review summarizes our current knowledge on the amyloid-generating propensity of traffic-related nanomaterials. Certain nanoparticles induce the amyloid aggregation of otherwise soluble proteins in in vitro laboratory settings, cultured neuronal cells and vertebrate or invertebrate animal models. We discuss the challenges for future studies, namely, strategies to connect the wet laboratory with the epidemiological data in order to elucidate the molecular bio-interactions of airborne nanomaterials and their effects on human health

Aging by pollutants: introducing the aging dose (AD)50

Abstract The global scale of environmental pollution and the accumulation of pollutants in environmental sinks such as soil and surface water sediments call for long-term investigation of relevant target organisms. Consistently, age-resolved toxicology in the nematode roundworm C. elegans revealed that effective concentrations of pollutants such as heavy metals and nanomaterials accelerate a variety of age-related phenotypes from reduced locomotion to amyloid protein aggregation and neurodegeneration. We suggest the definition of this acceleration by introduction of the aging dose (AD)50 that provides a new metric to characterize adverse effects of pollutants. AD50 represents any concentration of a pollutant that significantly accelerates an age-related defect in 50% of the exposed individuals. Comparison of pollutant-exposed with unexposed specimen concerning their age when 50% individuals display a specific aging phenotype indicates the time-frame of this acceleration and defines the corresponding reduction of health span. Application of AD50 is invented in the short-lived nematode C. elegans, however, provides for a research platform to better understand the role of pollutants in aging across different taxa. Toxicology that addresses the entire life span impacts both, environmental protection of wild fauna as well as health protection in the human population