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Isoflurane Increases Neuronal Cell Death Vulnerability by Downregulating miR-214  [PDF]
Hailiang Yan, Tao Xu, Hongfeng Zhao, Kuo-Chieh Lee, Hoau-Yan Wang, Yan Zhang
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055276
Abstract: Since accumulating evidence suggests the application of anesthetics may increase the risk of Alzheimer’s disease (AD), we investigated the cytotoxicity of inhaled general anesthesia in neurons and its underlying mechanism. Using primary cultured rat hippocampal neurons as the study model, here we show that isoflurane increases vulnerability to intracellular or extracellular amyloid β with or without serum deprivation. This isoflurane-induced effect is mediated by the downregulation of miR-214 level that lead to an elevated expression of Bax, a prominent target for miR-214. We conclude that isoflurane increases cell death in the presence of amyloid β by increasing Bax level through downregulating miR-214. Our data provide a new insight for inhaled anesthetics toxicity and indicate a possible mechanistic link between anesthetic application and neurodegenration in AD.
Drosophila Embryos as Model to Assess Cellular and Developmental Toxicity of Multi-Walled Carbon Nanotubes (MWCNT) in Living Organisms  [PDF]
Boyin Liu, Eva M. Campo, Torsten Bossing
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0088681
Abstract: Different toxicity tests for carbon nanotubes (CNT) have been developed to assess their impact on human health and on aquatic and terrestrial animal and plant life. We present a new model, the fruit fly Drosophila embryo offering the opportunity for rapid, inexpensive and detailed analysis of CNTs toxicity during embryonic development. We show that injected DiI labelled multi-walled carbon nanotubes (MWCNTs) become incorporated into cells in early Drosophila embryos, allowing the study of the consequences of cellular uptake of CNTs on cell communication, tissue and organ formation in living embryos. Fluorescently labelled subcellular structures showed that MWCNTs remained cytoplasmic and were excluded from the nucleus. Analysis of developing ectodermal and neural stem cells in MWCNTs injected embryos revealed normal division patterns and differentiation capacity. However, an increase in cell death of ectodermal but not of neural stem cells was observed, indicating stem cell-specific vulnerability to MWCNT exposure. The ease of CNT embryo injections, the possibility of detailed morphological and genomic analysis and the low costs make Drosophila embryos a system of choice to assess potential developmental and cellular effects of CNTs and test their use in future CNT based new therapies including drug delivery.
Silver nanoparticle toxicity in Drosophila: size does matter  [cached]
Deborah J Gorth,David M Rand,Thomas J Webster
International Journal of Nanomedicine , 2011,
Abstract: Deborah J Gorth1, David M Rand2, Thomas J Webster11School of Engineering, 2Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, USABackground: Consumer nanotechnology is a growing industry. Silver nanoparticles are the most common nanomaterial added to commercially available products, so understanding the influence that size has on toxicity is integral to the safe use of these new products. This study examined the influence of silver particle size on Drosophila egg development by comparing the toxicity of both nanoscale and conventional-sized silver particles.Methods: The toxicity assays were conducted by exposing Drosophila eggs to particle concentrations ranging from 10 ppm to 100 ppm of silver. Size, chemistry, and agglomeration of the silver particles were evaluated using transmission electron microscopy, X-ray photoelectron spectroscopy, and dynamic light scattering.Results: This analysis confirmed individual silver particle sizes in the ranges of 20–30 nm, 100 nm, and 500–1200 nm, with similar chemistry. Dynamic light scattering and transmission electron microscope data also indicated agglomeration in water, with the transmission electron microscopic images showing individual particles in the correct size range, but the dynamic light scattering z-average sizes of the silver nanoparticles were 782 ± 379 nm for the 20–30 nm silver nanoparticles, 693 ± 114 nm for the 100 nm silver nanoparticles, and 508 ± 32 nm for the 500–1200 nm silver particles. Most importantly, here we show significantly more Drosophila egg toxicity when exposed to larger, nonnanometer silver particles. Upon exposure to silver nanoparticles sized 20–30 nm, Drosophila eggs did not exhibit a statistically significant (P < 0.05) decrease in their likelihood to pupate, but eggs exposed to larger silver particles (500–1200 nm) were 91% ± 18% less likely to pupate. Exposure to silver nanoparticles reduced the percentage of pupae able to emerge as adults. At 10 ppm of silver particle exposure, only 57% ± 48% of the pupae exposed to 20–30 nm silver particles became adults, whereas 89% ± 25% of the control group became adults, and 94% ± 52% and 91% ± 19% of the 500–1200 nm and 100 nm group, respectively, reached adulthood.Conclusion: This research provides evidence that nanoscale silver particles (<100 nm) are less toxic to Drosophila eggs than silver particles of conventional (>100 nm) size.Keywords: Drosophila, silver, nanoparticle, toxicity
Silver nanoparticle toxicity in Drosophila: size does matter
Deborah J Gorth, David M Rand, Thomas J Webster
International Journal of Nanomedicine , 2011, DOI: http://dx.doi.org/10.2147/IJN.S16881
Abstract: nanoparticle toxicity in Drosophila: size does matter Original Research (7694) Total Article Views Authors: Deborah J Gorth, David M Rand, Thomas J Webster Published Date February 2011 Volume 2011:6 Pages 343 - 350 DOI: http://dx.doi.org/10.2147/IJN.S16881 Deborah J Gorth1, David M Rand2, Thomas J Webster1 1School of Engineering, 2Department of Ecology and Evolutionary Biology, Brown University, Providence, RI, USA Background: Consumer nanotechnology is a growing industry. Silver nanoparticles are the most common nanomaterial added to commercially available products, so understanding the influence that size has on toxicity is integral to the safe use of these new products. This study examined the influence of silver particle size on Drosophila egg development by comparing the toxicity of both nanoscale and conventional-sized silver particles. Methods: The toxicity assays were conducted by exposing Drosophila eggs to particle concentrations ranging from 10 ppm to 100 ppm of silver. Size, chemistry, and agglomeration of the silver particles were evaluated using transmission electron microscopy, X-ray photoelectron spectroscopy, and dynamic light scattering. Results: This analysis confirmed individual silver particle sizes in the ranges of 20–30 nm, 100 nm, and 500–1200 nm, with similar chemistry. Dynamic light scattering and transmission electron microscope data also indicated agglomeration in water, with the transmission electron microscopic images showing individual particles in the correct size range, but the dynamic light scattering z-average sizes of the silver nanoparticles were 782 ± 379 nm for the 20–30 nm silver nanoparticles, 693 ± 114 nm for the 100 nm silver nanoparticles, and 508 ± 32 nm for the 500–1200 nm silver particles. Most importantly, here we show significantly more Drosophila egg toxicity when exposed to larger, nonnanometer silver particles. Upon exposure to silver nanoparticles sized 20–30 nm, Drosophila eggs did not exhibit a statistically significant (P < 0.05) decrease in their likelihood to pupate, but eggs exposed to larger silver particles (500–1200 nm) were 91% ± 18% less likely to pupate. Exposure to silver nanoparticles reduced the percentage of pupae able to emerge as adults. At 10 ppm of silver particle exposure, only 57% ± 48% of the pupae exposed to 20–30 nm silver particles became adults, whereas 89% ± 25% of the control group became adults, and 94% ± 52% and 91% ± 19% of the 500–1200 nm and 100 nm group, respectively, reached adulthood. Conclusion: This research provides evidence that nanoscale silver particles (<100 nm) are less toxic to Drosophila eggs than silver particles of conventional (>100 nm) size.
Environmental Changes and Social Vulnerability in an Ageing Society: Portugal in the Transition from the 20th to the 21st Centuries
Maria Jo?o Guardado Moreira
Hygiea Internationalis : an Interdisciplinary Journal for the History of Public Health , 2010,
Abstract: One of the main structural changes human societies are actually facing relies on demographic ageing process, with strong impacts on health system and quality of life. Social and environmental factors can be used as predictors for health conditions, functional and cognitive autonomy, wellbeing and satisfaction on older ages. Reduced incomes, low educational level, situation of loneliness, can also be pointed as predictive factors of a major and premature deterioration of health. The adaptation of social structures must be a priority for all ageing societies. Portugal will also have to find answers to these challenges. The main objective of this study is to understand the process of vulnerability and multiple dependency situations caused by changes in the Portuguese demographic structure, manly regarding old people, as concerns the following aspects: a) levels of well-being in ageing regions determined by a statistical indicator; b) specific health care and long-term care.
Increases in norepinephrine release and ovarian cyst formation during ageing in the rat
Eric Acu?a, Romina Fornes, Daniela Fernandois, Maritza P Garrido, Monika Greiner, Hernan E Lara, Alfonso H Paredes
Reproductive Biology and Endocrinology , 2009, DOI: 10.1186/1477-7827-7-64
Abstract: Sprague-Dawley rats between 6 and 14 months old were used to analyse the capacity of the ovary to release 3H-NE recently incorporated under transmural depolarisation in relation to changes in the ovarian follicular population. Morphometric analysis of ovarian follicles and real time PCR for Bcl2 and Bax mRNA were used to assess follicular atresia.From 8 months old, the induced release of recently incorporated 3H-norepinephrine (3H-NE) from the ovary and ovarian NE concentrations increased, reaching their peak values at 12 months old and remained elevated up to 14 months old. Increases in sympathetic nerve activity paralleled changes in the follicular population, as well as disappearance of the corpus luteum. In contrast, luteinised follicles, precystic follicles, and cystic follicles increased. During this period, the relationship between Bax and Bcl2 mRNAs (the proapoptotic/antiapoptotic signals) increased, suggesting atresia as the principal mechanism contributing to the decreased follicular population. When NE tone was increased, the mRNA ratio favoured Bcl2 to Bax and antiapoptotic signals dominated this period of development. Thus, these changing ratios could be responsible for the increase in luteinised follicles, as well as precystic and cystic follicles.These data suggest that the ageing process in the ovary of the Sprague-Dawley rat is accompanied by an increased sympathetic tone of the ovary. Consequently, this sympathetic change could be related to a neuroendocrine-driven formation of a polycystic condition similar to that observed in the sympathetic-activated adult ovary.Reproductive senescence in mammals is a poorly understood process. Moreover, understanding the mechanism underlying the loss of ovarian function is especially important because of an increasingly aged population and the fact that pregnancy has been postponed continuously during recent decades [1,2]. Diverse hypotheses for age-related dysfunction have been postulated. The loss of reproduc
Detrimental Effects of RNAi: A Cautionary Note on Its Use in Drosophila Ageing Studies  [PDF]
Nazif Alic, Matthew P. Hoddinott, Andrea Foley, Cathy Slack, Matthew D. W. Piper, Linda Partridge
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0045367
Abstract: RNA interference (RNAi) provides an important tool for gene function discovery. It has been widely exploited in Caenorhabditis elegans ageing research because it does not appear to have any non-specific effects on ageing-related traits in that model organism. We show here that ubiquitous, adult-onset activation of the RNAi machinery, achieved by expressing a double stranded RNA targeting GFP or lacZ for degradation, or by increasing expression of Dicer substantially reduces lifespan in Drosophila melanogaster. Induction of GFPRNAi construct also alters the response of lifespan to nutrition, exacerbating the lifespan-shortening effects of food containing a high quantity of yeast. Our study indicates that activation of the RNAi machinery may have sequence-independent side-effects on lifespan, and that caution needs to be exercised when employing ubiquitous RNAi in Drosophila ageing studies. However, we also show that RNAi restricted to certain tissues may not be detrimental to lifespan.
Immunity & Ageing: a new journal looking at ageing from an immunological point of view
Sonya Vasto, Calogero Caruso
Immunity & Ageing , 2004, DOI: 10.1186/1742-4933-1-1
Abstract: Immunity & Ageing is a new Open Access, peer reviewed journal that aims to provide a forum for articles examining ageing from an immunological point of view.During the past century, humans have gained more years of average life expectancy than in the last 10,000 years; we are now living in a rapidly ageing world. The sharp rise in life expectancy, coupled to a steady decline in birth rates in all developed countries, has led to an unprecedented demographic revolution characterized by an explosive growth in the number and proportion of older people. The number of people aged 60 years or older exceeded 635 million in 2002, and is expected to grow to nearly 2 billion by 2050. The proportion of people aged 60 and over stands about 1 in 4 in many Western European countries as well as in Japan. Should the present trend continues, this ratio is expected to reach 1 in 3 by 2050 [1]. Among the aged, the oldest old (>85) make up the fastest growing category. As access to medical care improves worldwide, the rate of population ageing will accelerate. If global communications is making the world "young and fast", then global ageing is surely "maturing and slowing" it. In any case, these epidemiological facts underscore the importance of studies on successful and unsuccessful ageing and necessitate the prompt spread of knowledge about ageing in order to satisfactorily decrease the medical, economic and social problems associated with advancing years.Ageing is a post-maturational process that, due to a diminished homeostatic capacity and increased vulnerability, reduces responsiveness to environmental stimuli and is generally associated with an increased predisposition to illness and death. At the beginning of the 19th century, mortality was described as increasing exponentially with respect to progression through the lifespan [2]. This trend, also described in invertebrates, persists: in Western countries the mortality rate increases 25 times more rapidly in individuals over 60
Aconitase Causes Iron Toxicity in Drosophila pink1 Mutants  [PDF]
Giovanni Esposito,Melissa Vos,Sven Vilain,Jef Swerts,Jorge De Sousa Valadas,Stefanie Van Meensel,Onno Schaap,Patrik Verstreken
PLOS Genetics , 2013, DOI: 10.1371/journal.pgen.1003478
Abstract: The PTEN-induced kinase 1 (PINK1) is a mitochondrial kinase, and pink1 mutations cause early onset Parkinson's disease (PD) in humans. Loss of pink1 in Drosophila leads to defects in mitochondrial function, and genetic data suggest that another PD-related gene product, Parkin, acts with pink1 to regulate the clearance of dysfunctional mitochondria (mitophagy). Consequently, pink1 mutants show an accumulation of morphologically abnormal mitochondria, but it is unclear if other factors are involved in pink1 function in vivo and contribute to the mitochondrial morphological defects seen in specific cell types in pink1 mutants. To explore the molecular mechanisms of pink1 function, we performed a genetic modifier screen in Drosophila and identified aconitase (acon) as a dominant suppressor of pink1. Acon localizes to mitochondria and harbors a labile iron-sulfur [4Fe-4S] cluster that can scavenge superoxide to release hydrogen peroxide and iron that combine to produce hydroxyl radicals. Using Acon enzymatic mutants, and expression of mitoferritin that scavenges free iron, we show that [4Fe-4S] cluster inactivation, as a result of increased superoxide in pink1 mutants, results in oxidative stress and mitochondrial swelling. We show that [4Fe-4S] inactivation acts downstream of pink1 in a pathway that affects mitochondrial morphology, but acts independently of parkin. Thus our data indicate that superoxide-dependent [4Fe-4S] inactivation defines a potential pathogenic cascade that acts independent of mitophagy and links iron toxicity to mitochondrial failure in a PD–relevant model.
Genetic and Chemical Modifiers of a CUG Toxicity Model in Drosophila  [PDF]
Amparo Garcia-Lopez, Lidon Monferrer, Irma Garcia-Alcover, Marta Vicente-Crespo, M. Carmen Alvarez-Abril, Ruben D. Artero
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001595
Abstract: Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively. These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal anti-inflammatory agents (ketoprofen), muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine), and drugs that can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights into the DM1 phenotype, and suggest novel candidates for DM1 treatments.
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