Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-10 (of 10 Records) |
Query Trace: Pacurari M[original query] |
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Acute vibration induces peripheral nerve sensitization in a rat tail model: Possible role of oxidative stress and inflammation
Pacurari M , Waugh S , Krajnak K . Neuroscience 2018 398 263-272 Prolonged occupational exposure to hand-held vibrating tools leads to pain and reductions in tactile sensitivity, grip strength and manual dexterity. The goal of the current study was to use a rat-tail vibration model to determine how vibration frequency influences factors related to nerve injury and dysfunction. Rats were exposed to restraint, or restraint plus tail vibration at 62.5 Hz or 250 Hz. Nerve function was assessed using the current perception threshold (CPT) test. Exposure to vibration at 62.5 and 250 Hz, resulted in a reduction in the CPT at 2000 and 250 Hz electrical stimulation (i.e. increased Abeta and Adelta, nerve fiber sensitivity). Vibration exposure at 250 Hz also resulted in an increased sensitivity of C-fibers to electrical stimulation and thermal nociception. These changes in nerve fiber sensitivity were associated with increased expression of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha in ventral tail nerves, and increases in circulating concentrations of IL-1 beta in rats exposed to 250 Hz vibration. There was an increase in glutathione, but no changes in other measures of oxidative activity in the peripheral nerve. However, measures of oxidative stress were increased in the dorsal root ganglia (DRG). These changes in pro-inflammatory factors and markers of oxidative stress in the peripheral nerve and DRG were associated with inflammation, and reductions in myelin basic protein and post-synaptic density protein (PSD)-95 gene expression, suggesting that vibration induced changes in sensory function may be the result of changes at the exposed nerve, the DRG and/or the spinal cord. |
System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses
Snyder-Talkington BN , Dymacek J , Porter DW , Wolfarth MG , Mercer RR , Pacurari M , Denvir J , Castranova V , Qian Y , Guo NL . Toxicol Appl Pharmacol 2013 272 (2) 476-89 The fibrous shape and biopersistence of multi-walled carbon nanotubes (MWCNT) have raised concern over their potential toxicity after pulmonary exposure. As in vivo exposure to MWCNT produced a transient inflammatory and progressive fibrotic response, this study sought to identify significant biological processes associated with lung inflammation and fibrosis pathology data, based upon whole genome mRNA expression, bronchoaveolar lavage scores, and morphometric analysis from C57BL/6J mice exposed by pharyngeal aspiration to 0, 10, 20, 40, or 80mug MWCNT at 1, 7, 28, or 56days post-exposure. Using a novel computational model employing non-negative matrix factorization and Monte Carlo Markov Chain simulation, significant biological processes with expression similar to MWCNT-induced lung inflammation and fibrosis pathology data in mice were identified. A subset of genes in these processes was determined to be functionally related to either fibrosis or inflammation by Ingenuity Pathway Analysis and was used to determine potential significant signaling cascades. Two genes determined to be functionally related to inflammation and fibrosis, vascular endothelial growth factor A (vegfa) and C-C motif chemokine 2 (ccl2), were confirmed by in vitro studies of mRNA and protein expression in small airway epithelial cells exposed to MWCNT as concordant with in vivo expression. This study identified that the novel computational model was sufficient to determine biological processes strongly associated with the pathology of lung inflammation and fibrosis and could identify potential toxicity signaling pathways and mechanisms of MWCNT exposure which could be used for future animal studies to support human risk assessment and intervention efforts. |
The microRNA-200 family targets multiple non-small cell lung cancer prognostic markers in H1299 cells and BEAS-2B cells.
Pacurari M , Addison JB , Bondalapati N , Wan YW , Luo D , Qian Y , Castranova V , Ivanov AV , Guo NL . Int J Oncol 2013 43 (2) 548-60 Lung cancer remains the leading cause of cancer-related mortality for both men and women. Tumor recurrence and metastasis is the major cause of lung cancer treatment failure and death. The microRNA200 (miR-200) family is a powerful regulator of the epithelial-mesenchymal transition (EMT) process, which is essential in tumor metastasis. Nevertheless, miR-200 family target genes that promote metastasis in non-small cell lung cancer (NSCLC) remain largely unknown. Here, we sought to investigate whether the microRNA-200 family regulates our previously identified NSCLC prognostic marker genes associated with metastasis, as potential molecular targets. Novel miRNA targets were predicted using bioinformatics tools based on correlation analyses of miRNA and mRNA expression in 57 squamous cell lung cancer tumor samples. The predicted target genes were validated with quantitative RT-PCR assays and western blot analysis following re-expression of miR-200a, -200b and -200c in the metastatic NSCLC H1299 cell line. The results show that restoring miR-200a or miR-200c in H1299 cells induces downregulation of DLC1, ATRX and HFE. Reinforced miR-200b expression results in downregulation of DLC1, HNRNPA3 and HFE. Additionally, miR-200 family downregulates HNRNPR3, HFE and ATRX in BEAS-2B immortalized lung epithelial cells in quantitative RT-PCR and western blot assays. The miR-200 family and these potential targets are functionally involved in canonical pathways of immune response, molecular mechanisms of cancer, metastasis signaling, cell-cell communication, proliferation and DNA repair in Ingenuity pathway analysis (IPA). These results indicate that re-expression of miR-200 downregulates our previously identified NSCLC prognostic biomarkers in metastatic NSCLC cells. These results provide new insights into miR-200 regulation in lung cancer metastasis and consequent clinical outcome, and may provide a potential basis for innovative therapeutic approaches for the treatment of this deadly disease. |
Systematic analysis of multiwalled carbon nanotube-induced cellular signaling and gene expression in human small airway epithelial cells.
Snyder-Talkington BN , Pacurari M , Dong C , Leonard SS , Schwegler-Berry D , Castranova V , Qian Y , Guo NL . Toxicol Sci 2013 133 (1) 79-89 Multi-walled carbon nanotubes (MWCNT) are one of the most commonly produced nanomaterials, and pulmonary exposure during production, use, and disposal is a concern for the developing nanotechnology field. The airway epithelium is the first line of defense against inhaled particles. In a mouse model, MWCNT were reported to reach the alveolar space of the lung after in vivo exposure, penetrate the epithelial lining, and result in inflammation and progressive fibrosis. This study sought to determine the cellular and gene expression changes in small airway epithelial cells (SAEC) after in vitro exposure to MWCNT in an effort to elucidate potential toxicity mechanisms and signaling pathways. A direct interaction between SAEC and MWCNT was confirmed by both internalization of MWCNT as well as an interaction at the cell periphery. Following exposure, SAEC showed time-dependent increases in reactive oxygen species production, total protein phospho-tyrosine and phospho-threonine levels, and migratory behavior. Analysis of gene and protein expression suggested altered regulation of multiple biomarkers of lung damage, carcinogenesis, and tumor progression, as well as genes involved in related signaling pathways. These results demonstrate that MWCNT exposure resulted in the activation of SAEC. Gene expression data derived from MWCNT exposure provides information that may be used to elucidate the underlying mode of action of MWCNT in the small airway and suggest potential prognostic gene signatures for risk assessment. |
Multiwalled carbon nanotube-induced gene signatures in the mouse lung: potential predictive value for human lung cancer risk and prognosis.
Guo NL , Wan YW , Denvir J , Porter DW , Pacurari M , Wolfarth MG , Castranova V , Qian Y . J Toxicol Environ Health A 2012 75 (18) 1129-53 Concerns over the potential for multiwalled carbon nanotubes (MWCNT) to induce lung carcinogenesis have emerged. This study sought to (1) identify gene expression signatures in the mouse lungs following pharyngeal aspiration of well-dispersed MWCNT and (2) determine if these genes were associated with human lung cancer risk and progression. Genome-wide mRNA expression profiles were analyzed in mouse lungs (n = 160) exposed to 0, 10, 20, 40, or 80 mcg of MWCNT by pharyngeal aspiration at 1, 7, 28, and 56 d postexposure. By using pairwise statistical analysis of microarray (SAM) and linear modeling, 24 genes were selected, which have significant changes in at least two time points, have a more than 1.5-fold change at all doses, and are significant in the linear model for the dose or the interaction of time and dose. Additionally, a 38-gene set was identified as related to cancer from 330 genes differentially expressed at d 56 postexposure in functional pathway analysis. Using the expression profiles of the cancer-related gene set in 8 mice at d 56 postexposure to 10 mcg of MWCNT, a nearest centroid classification accurately predicts human lung cancer survival with a significant hazard ratio in training set (n = 256) and test set (n = 186). Furthermore, both gene signatures were associated with human lung cancer risk (n = 164) with significant odds ratios. These results may lead to development of a surveillance approach for early detection of lung cancer and prognosis associated with MWCNT in the workplace. |
Cell permeability, migration, and reactive oxygen species induced by multiwalled carbon nanotubes in human microvascular endothelial cells
Pacurari M , Qian Y , Fu W , Schwegler-Berry D , Ding M , Castranova V , Guo NL . J Toxicol Environ Health A 2012 75 (3) 129-47 Multiwalled carbon nanotubes (MWCNT) have elicited great interest in biomedical applications due to their extraordinary physical, chemical, and optical properties. Intravenous administration of MWCNT-based medical imaging agents and drugs in animal models was utilized. However, the potential harmful health effects of MWCNT administration in humans have not yet been elucidated. Furthermore, to date, there are no apparent reports regarding the precise mechanisms of translocation of MWCNT into target tissues and organs from blood circulation. This study demonstrates that exposure to MWCNT leads to an increase in cell permeability in human microvascular endothelial cells (HMVEC). The results obtained from this study also showed that the MWCNT-induced rise in endothelial permeability is mediated by reactive oxygen species (ROS) production and actin filament remodeling. In addition, it was found that MWCNT promoted cell migration in HMVEC. Mechanistically, MWCNT exposure elevated the levels of monocyte chemoattractant protein-1 (MCP-1) and intercellular adhesion molecule 1 (ICAM-1) in HMVEC. Taken together, these results provide new insights into the bioreactivity of MWCNT, which may have implications in the biomedical application of MWCNT in vascular targeting, imaging, and drug delivery. The results generated from this study also elucidate the potential adverse effects of MWCNT exposure on humans at the cellular level. |
Multi-walled carbon nanotube-induced gene expression in the mouse lung: association with lung pathology.
Pacurari M , Qian Y , Porter DW , Wolfarth M , Wan Y , Luo D , Ding M , Castranova V , Guo NL . Toxicol Appl Pharmacol 2011 255 (1) 18-31 Due to the fibrous shape and durability of multi-walled carbon nanotubes (MWCNT), concerns regarding their potential for producing environmental and human health risks, including carcinogenesis, have been raised. This study sought to investigate how previously identified lung cancer prognostic biomarkers and the related cancer signaling pathways are affected in the mouse lung following pharyngeal aspiration of well-dispersed MWCNT. A total of 63 identified lung cancer prognostic biomarker genes and major signaling biomarker genes were analyzed in mouse lungs (n=80) exposed to 0, 10, 20, 40, or 80mug of MWCNT by pharyngeal aspiration at 7 and 56days post-exposure using quantitative PCR assays. At 7 and 56days post-exposure, a set of 7 genes and a set of 11 genes, respectively, showed differential expression in the lungs of mice exposed to MWCNT vs. the control group. Additionally, these significant genes could separate the control group from the treated group over the time series in a hierarchical gene clustering analysis. Furthermore, 4 genes from these two sets of significant genes, coiled-coil domain containing-99 (Ccdc99), muscle segment homeobox gene-2 (Msx2), nitric oxide synthase-2 (Nos2), and wingless-type inhibitory factor-1 (Wif1), showed significant mRNA expression perturbations at both time points. It was also found that the expression changes of these 4 overlapping genes at 7days post-exposure were attenuated at 56days post-exposure. Ingenuity Pathway Analysis (IPA) found that several carcinogenic-related signaling pathways and carcinogenesis itself were associated with both the 7 and 11 gene signatures. Taken together, this study identifies that MWCNT exposure affects a subset of lung cancer biomarkers in mouse lungs. |
Raw single-walled carbon nanotube-induced cytotoxic effects in human bronchial epithelial cells: comparison to asbestos
Pacurari M , Schwegler-Berry D , Friend S , Leonard SS , Mercer RR , Vallyathan V , Castranova V . Toxicol Environ Chem 2011 93 (5) 1045-1072 Single-walled carbon nanotubes (SWCNT) are being developed to be used in many industrial and biomedical applications. However, SWCNT's durability and likely fibrous morphology have raised health concerns. The present investigations were focused on understanding the cellular and molecular mechanisms induced by raw SWCNT (SWCNT) in human bronchial-epithelial cells (BEAS-2B). Asbestos (crocidolite) was used as a positive control. Exposure of BEAS-2B cells to SWCNT induced apoptosis, DNA damage, and oxidative stress. The generation of hydroxyl radical (center dot OH) and increase of superoxide dismutase (SOD) activity were concentration-dependent. The increase in apoptosis was associated with activation of caspase-3, caspase-7, and poly (ADP-ribose) polymerase-1 (PARP-1). A short recovery period of 6 h of cells from SWCNT exposure resulted in reversal of caspase-3 and caspase-7, and a partial reversal of PARP-1 activation. The activation of PARP-1, caspase-3, and caspase-7 was only partially diminished after a recovery of 6 h from the exposure to crocidolite. Exposure of BEAS-2B cells to SWCNT resulted in the phosphorylation of protein p42/44 (p42/44) and protein p38 (p38). SWCNT did not induce protein serine-threonine kinase (AKT) phosphorylation. For all the above end points, crocidolite induced a greater response compared to SWCNT. SWCNT induced a significant activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-B), and the effect was inhibited by mitogen-activated protein kinase (MAPK) inhibitors. SWCNT also induced significant increase in the expression levels of c-Jun, IGH3, and CD44 genes. The results of this study show that the molecular mechanism for raw SWCNT-mediated toxicity in BEAS-2B cells is through the activation of caspase-3, caspase-7, and PARP-1. Furthermore, the mechanism of AP-1 and NF-B activation is through MAPK. This bioactivity of raw SWCNT is associated with the generation of oxidative stress and DNA damage. Considering the role of airway epithelium as a critical barrier for normal pulmonary function and focal point for tumor development, this study demonstrates that raw SWCNT activate molecular events which may be linked to adverse biological responses implicated in pulmonary diseases. |
Single- and multi-wall carbon nanotubes versus asbestos: are the carbon nanotubes a new health risk to humans?
Pacurari M , Castranova V , Vallyathan V . J Toxicol Environ Health A 2010 73 (5) 378-95 Carbon nanotubes (CNT), since their discovery, have become one of the most promising nanomaterials in many industrial and biomedical applications. Due to their unique physicochemical properties, interest is growing in the manufacture of CNT-based products and their subsequent marketing. Since their discovery, the prospect of possible undesirable human health effects has been a focus of many scientific studies. Although CNT possess unique physical properties that include (1) nanoscale diameter, (2) a wide length distribution ranging from tens of nanometers to several micrometers, and (3) high aspect ratio, the fibrous-like shape and durability suggest that their toxic properties may be analogous to those observed with other fibrous particles, such as asbestos. The present study provides a summary of published findings on CNT bioactivity, such as the potential of CNT, especially of multi-wall carbon nanotubes (MWCNT), to activate signaling pathways modulating transcription factor activity, induce apoptosis, induce DNA damage, and initiate biological responses. Assessment of risks to human health and adoption of appropriate exposure controls is critical for the safe and successful introduction of CNT -based products for future applications. |
DNA double strand breaks by asbestos, silica and titanium dioxide: possible biomarker of carcinogenic potential?
Msiska Z , Pacurari M , Mishra A , Leonard SS , Castranova V , Vallyathan V . Am J Respir Cell Mol Biol 2009 43 (2) 210-9 DNA double strand breaks (DNA DSBs) are a very rapid response to DNA damage that occurs in cells subjected to radiation, exposure to toxic substances, and other environmental stresses. The inability to repair these breaks can lead to carcinogenesis. One of the earliest responses to DNA DSBs is the phosphorylation of a histone, H2AX, at serine 139, yielding a focal product (gamma-H2AX) that can be detected by a fluorescent antibody. A study was undertaken to compare the induction of DNA DSBs in normal (SAE) and cancer cells (A549) after exposure to asbestos (crocidolite), a proven carcinogen, silica a suspected carcinogen, and titanium dioxide (an inert particle, recently reported to be carcinogenic in animals). The results indicate that crocidolite induced greater DNA DSBs than silica and TiO2 regardless of cell type. DNA DSBs due to crocidolite were higher in normal cells than in cancer cells. Silica and TiO2 induced higher DNA DSBs in cancer cells than in normal cells. The production of reactive oxygen species (ROS) was found to be highest in cells exposed to crocidolite followed in potency by silica and TiO2. The generation of ROS was higher in normal cells than in cancer cells. Cell viability assay indicated that crocidolite caused the greatest cytotoxicity in both cell types. Apoptosis, measured by caspase 3/7 activity, was highest in crocidolite-exposed cells followed in potency by TiO2 and silica. The results of this study indicate that crocidolite has a greater carcinogenic potential than silica and TiO2 judged by its ability to cause sustained genomic instability in normal lung cells. |
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