Contemporary Insights into the Biological Mechanisms of Parkia biglobosa.

For a long time, traditional medicine has relied on the use of medicinal plants and herbal products which have served as the basis for numerous pharmaceuticals. Parkia biglobosa (Jacq) R.Br.ex. G. Don., commonly called the African locust bean tree, is a perennial deciduous plant native to West Africa where it is highly esteemed for its nutritional and traditional medicinal benefits. Parkia biglobosa's ethnomedicinal uses include microbial infections such as diarrhea and chronic diseases like hypertension and type 2 diabetes mellitus. This article presents the current understanding of the molecular mechanisms underlying Parkia biglobosa's biological effects. An electronic database search was conducted using P. biglobosa and its synonyms as keywords in Scientific Electronic Library Online, ISI Web of Knowledge, PubMed, Scopus, Science Direct, and Google Scholar. Consistently, scientific research has confirmed the medicinal effects of the plant's extracts and active phytochemicals, including antimicrobial, analgesic, antidiabetic, antihypertensive, hypolipidemic, and neuroprotective properties, among others. It highlights the contributions of identified innate phytochemicals and existing limitations to therapeutic applications, as well as the need for and prospects for further research. Advancing our understanding of the medicinal plant's biological mechanisms and the contributions of the active phytochemicals would allow for more effective exploration of its vast pharmacological potential and facilitate clinical applications.

CXC Chemokines in the Pathogenesis of Pulmonary Disease and Pharmacological Relevance.

Chemokines and their receptors play important roles in the pathophysiology of many diseases by regulating the cellular migration of major inflammatory and immune players. The CXC motif chemokine subfamily is the second largest family, and it is further subdivided into ELR motif CXC (ELR+) and non-ELR motif (ELR-) CXC chemokines, which are effective chemoattractants for neutrophils and lymphocytes/monocytes, respectively. These chemokines and their receptors are expected to have a significant impact on a wide range of lung diseases, many of which have inflammatory or immunological underpinnings. As a result, manipulations of this subfamily of chemokines and their receptors using small molecular agents and other means have been explored for potential therapeutic benefit in the setting of several lung pathologies. Furthermore, encouraging preclinical data has necessitated the progression of a few of these drugs into clinical trials in order to make the most effective use of interventions in the development of viable targeted therapeutics. The current review presents the understanding of the roles of CXC ligands (CXCLs) and their cognate receptors (CXCRs) in the pathogenesis of several lung diseases such as allergic rhinitis, COPD, lung fibrosis, lung cancer, pneumonia, and tuberculosis. The potential therapeutic benefits of pharmacological or other CXCL/CXCR axis manipulations are also discussed.

Idiopathic Pulmonary Comorbidities and Mechanisms.

Idiopathic pulmonary fibrosis (IPF) is a disease with an unknown etiology mainly characterized by a progressive decline of lung function due to the scarring of the tissue deep in the lungs. The overall survival after diagnosis remains low between 3 and 5 years. IPF is a heterogeneous disease and much progress has been made in the past decade in understanding the disease mechanisms that contributed to the development of two new drugs, pirfenidone and nintedanib, which improved the therapeutic management of the disease. The understanding of the cofactors and comorbidities of IPF also contributed to improved management of the disease outcome. In the present review, we evaluate scientific evidence which indicates IPF as a risk factor for other diseases based on the complexity of molecular and cellular mechanisms involved in the disease development and of comorbidities. We conclude from the existing literature that while much progress has been made in understating the mechanisms involved in IPF development, further studies are still necessary to fully understand IPF pathogenesis which will contribute to the identification of novel therapeutic targets for IPF management as well as other diseases for which IPF is a major risk factor.

State of the science review of the health effects of inorganic arsenic: Perspectives for future research.

Human exposure to inorganic arsenic (iAs) is a global health issue. Although there is strong evidence for iAs-induced toxicity at higher levels of exposure, many epidemiological studies evaluating its effects at low exposure levels have reported mixed results. We comprehensively reviewed the literature and evaluated the scientific knowledge on human exposure to arsenic, mechanisms of action, systemic and carcinogenic effects, risk characterization, and regulatory guidelines. We identified areas where additional research is needed. These priority areas include: (1) further development of animal models of iAs carcinogenicity to identify molecular events involved in iAs carcinogenicity; (2) characterization of underlying mechanisms of iAs toxicity; (3) assessment of gender-specific susceptibilities and other factors that modulate arsenic metabolism; (4) sufficiently powered epidemiological studies to ascertain relationship between iAs exposure and reproductive/developmental effects; (5) evaluation of genetic/epigenetic determinants of iAs effects in children; and (6) epidemiological studies of people chronically exposed to low iAs concentrations.

A Review on the Respiratory System Toxicity of Carbon Nanoparticles.

The respiratory system represents the main gateway for nanoparticles' entry into the human body. Although there is a myriad of engineered nanoparticles, carbon nanoparticles/nanotubes (CNPs/CNTs) have received much attention mainly due to their light weight, very high surface area, durability, and their diverse applications. Since their discovery and manufacture over two decades ago, much has been learned about nanoparticles' interactions with diverse biological system models. In particular, the respiratory system has been of great interest because various natural and man-made fibrous particles are known to be responsible for chronic and debilitating lung diseases. In this review, we present up-to-date the literature regarding the effects of CNTs or carbon nanofibers (CNFs) on the human respiratory system with respect to respiratory toxicity pathways and associated pathologies. This article is intended to emphasize the potentially dangerous effects to the human respiratory system if inadequate measures are used in the manufacture, handling, and preparation and applications of CNP or CNP-based products.

Secondary Data Analytics of Aquaporin Expression Levels in Glioblastoma Stem-Like Cells.

Glioblastoma is the most common brain tumor in adults in which recurrence has been attributed to the presence of cancer stem cells in a hypoxic microenvironment. On the basis of tumor formation in vivo and growth type in vitro, two published microarray gene expression profiling studies grouped nine glioblastoma stem-like (GS) cell lines into one of two groups: full (GSf) or restricted (GSr) stem-like phenotypes. Aquaporin-1 (AQP1) and aquaporin-4 (AQP4) are water transport proteins that are highly expressed in primary glial-derived tumors. However, the expression levels of AQP1 and AQP4 have not been previously described in a panel of 92 glioma samples. Therefore, we designed secondary data analytics methods to determine the expression levels of AQP1 and AQP4 in GS cell lines and glioblastoma neurospheres. Our investigation also included a total of 2,566 expression levels from 28 Affymetrix microarray probe sets encoding 13 human aquaporins (AQP0-AQP12); CXCR4 (the receptor for stromal cell derived factor-1 [SDF-1], a potential glioma stem cell therapeutic target]); and PROM1 (gene encoding CD133, the widely used glioma stem cell marker). Interactive visual representation designs for integrating phenotypic features and expression levels revealed that inverse expression levels of AQP1 and AQP4 correlate with distinct phenotypes in a set of cell lines grouped into full and restricted stem-like phenotypes. Discriminant function analysis further revealed that AQP1 and AQP4 expression are better predictors for tumor formation and growth types in glioblastoma stem-like cells than are CXCR4 and PROM1. Future investigations are needed to characterize the molecular mechanisms for inverse expression levels of AQP1 and AQP4 in the glioblastoma stem-like neurospheres.

Role of MicroRNAs in Renin-Angiotensin-Aldosterone System-Mediated Cardiovascular Inflammation and Remodeling.

MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS-) mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s) of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA-regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS-mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling.

The Renin-Angiotensin-aldosterone system in vascular inflammation and remodeling.

The RAAS through its physiological effectors plays a key role in promoting and maintaining inflammation. Inflammation is an important mechanism in the development and progression of CVD such as hypertension and atherosclerosis. In addition to its main role in regulating blood pressure and its role in hypertension, RAAS has proinflammatory and profibrotic effects at cellular and molecular levels. Blocking RAAS provides beneficial effects for the treatment of cardiovascular and renal diseases. Evidence shows that inhibition of RAAS positively influences vascular remodeling thus improving CVD outcomes. The beneficial vascular effects of RAAS inhibition are likely due to decreasing vascular inflammation, oxidative stress, endothelial dysfunction, and positive effects on regeneration of endothelial progenitor cells. Inflammatory factors such as ICAM-1, VCAM-1, TNFα, IL-6, and CRP have key roles in mediating vascular inflammation and blocking RAAS negatively modulates the levels of these inflammatory molecules. Some of these inflammatory markers are clinically associated with CVD events. More studies are required to establish long-term effects of RAAS inhibition on vascular inflammation, vascular cells regeneration, and CVD clinical outcomes. This review presents important information on RAAS's role on vascular inflammation, vascular cells responses to RAAS, and inhibition of RAAS signaling in the context of vascular inflammation, vascular remodeling, and vascular inflammation-associated CVD. Nevertheless, the review also equates the need to rethink and rediscover new RAAS inhibitors.

Di-ethylhexylphthalate (DEHP) modulates cell invasion, migration and anchorage independent growth through targeting S100P in LN-229 glioblastoma cells.

Glioblastoma multiforme (GBM) is the most aggressive brain cancer with a median survival of 1-2 years. The treatment of GBM includes surgical resection, radiation and chemotherapy, which minimally extends survival. This poor prognosis necessitates the identification of novel molecular targets associated with glioblastoma. S100P is associated with drug resistance, metastasis, and poor clinical outcomes in many malignancies. The functional role of S100P in glioblastoma has not been fully investigated. In this study, we examined the role of S100P mediating the effects of the environmental contaminant, DEHP, in glioblastoma cells (LN-229) by assessing cell proliferation, apoptosis, anchorage independent growth, cell migration and invasion following DEHP exposure. Silencing S100P and DEHP treatment inhibited LN-229 glioblastoma cell proliferation and induced apoptosis. Anchorage independent growth study revealed significantly decreased colony formation in shS100P cells. We also observed reduced cell migration in cells treated with DEHP following S100P knockdown. Similar results were observed in spheroid formation and expansion. This study is the first to demonstrate the effects of DEHP on glioblastoma cells, and implicates S100P as a potential therapeutic target that may be useful as a drug response biomarker.

Endothelial cell transfusion ameliorates endothelial dysfunction in 5/6 nephrectomized rats.

Endothelial dysfunction is prevalent in chronic kidney disease. This study tested the hypothesis that transfusion of rat aortic endothelial cells (ECs) ameliorates endothelial dysfunction in a rat model of chronic kidney disease. Male Sprague-Dawley rats underwent sham surgery or 5/6 nephrectomy (Nx). Five weeks after Nx, EC (1.5 × 10(6) cells/rat) or vehicle were transfused intravenously. One week later, vascular reactivity of mesenteric artery was assessed on a wire myograph. Sensitivity of endothelium-dependent relaxation to acetylcholine and maximum vasodilation were impaired by Nx and improved by EC transfusion. Using selective pharmacological nitric oxide synthase isoform inhibitors, we demonstrated that the negative effect of Nx on endothelial function and rescue by EC transfusion are, at least in part, endothelial nitric oxide synthase mediated. Plasma asymmetric dimethylarginine was increased by Nx and decreased by EC transfusion, whereas mRNA expression of dimethylarginine dimethylaminohydrolases 1 (DDAH1) was decreased by Nx and restored by EC transfusion. Immunohistochemical staining confirmed that local expression of DDAH1 is decreased by Nx and increased by EC transfusion. In conclusion, EC transfusion attenuates Nx-induced endothelium-dependent vascular dysfunction by regulating DDAH1 expression and enhancing endothelial nitric oxide synthase activity. These results suggest that EC-based therapy could provide a novel therapeutic strategy to improve vascular function in chronic kidney disease.

System-based identification of toxicity pathways associated with multi-walled carbon nanotube-induced pathological responses.

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 80 µg MWCNT at 1, 7, 28, or 56 days 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.

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.

Multiwalled 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 and interaction at the cell periphery. Following exposure, SAEC showed time-dependent increases in reactive oxygen species production, total protein phosphotyrosine and phosphothreonine 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 provide 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.

Single-cell gel electrophoresis (Comet) assay in nano-genotoxicology.

The Comet assay, or single-cell gel electrophoresis assay, is an easy and simple yet reliable method to evaluate DNA damage in cells. Under the alkaline conditions of this method, DNA strand breaks and alkaline-labile sites are detected. Here we describe the alkaline version of the Comet assay with applications in testing nanoparticles.

Multiwalled carbon nanotube-induced gene signatures in the mouse lung: potential predictive value for human lung cancer risk and prognosis.

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 µg 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 µg 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.

Single- and multi-wall carbon nanotubes versus asbestos: are the carbon nanotubes a new health risk to humans?

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?

DNA double-strand breaks (DSBs) can result in cell death or genetic alterations when cells are subjected to radiation, exposure to toxins, or other environmental stresses. A complex DNA-damage-response pathway is activated to repair the damage, and 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 (gamma-H2AX), which can be detected by a fluorescent antibody. A study was undertaken to compare the induction of DNA DSBs in normal (small airway epithelial) cells and cancer cells (A549) after exposure to asbestos (crocidolite), a proven carcinogen, silica, a suspected carcinogen, and titanium dioxide (TiO(2)), an inert particle recently reported to be carcinogenic in animals. The results indicate that crocidolite induced greater DNA DSBs than silica and TiO(2), regardless of cell type. DNA DSBs caused by crocidolite were higher in normal cells than in cancer cells. Silica and TiO(2) induced higher DNA DSBs in cancer cells than in normal cells. The production of reactive oxygen species was found to be highest in cells exposed to crocidolite, followed, in potency, by silica and TiO(2). The generation of reactive oxygen species 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 and poly (ADP-Ribose) polymerase activation, was highest in crocidolite-exposed cells, followed by TiO(2) and silica. The results of this study indicate that crocidolite has a greater carcinogenic potential than silica and TiO(2), judged by its ability to cause sustained genomic instability in normal lung cells.

Iron oxide nanoparticles induce human microvascular endothelial cell permeability through reactive oxygen species production and microtubule remodeling.

BACKGROUND: Engineered iron nanoparticles are being explored for the development of biomedical applications and many other industry purposes. However, to date little is known concerning the precise mechanisms of translocation of iron nanoparticles into targeted tissues and organs from blood circulation, as well as the underlying implications of potential harmful health effects in human. RESULTS: The confocal microscopy imaging analysis demonstrates that exposure to engineered iron nanoparticles induces an increase in cell permeability in human microvascular endothelial cells. Our studies further reveal iron nanoparticles enhance the permeability through the production of reactive oxygen species (ROS) and the stabilization of microtubules. We also showed Akt/GSK-3beta signaling pathways are involved in iron nanoparticle-induced cell permeability. The inhibition of ROS demonstrate ROS play a major role in regulating Akt/GSK-3beta - mediated cell permeability upon iron nanoparticle exposure. These results provide new insights into the bioreactivity of engineered iron nanoparticles which can inform potential applications in medical imaging or drug delivery. CONCLUSION: Our results indicate that exposure to iron nanoparticles induces an increase in endothelial cell permeability through ROS oxidative stress-modulated microtubule remodeling. The findings from this study provide new understandings on the effects of nanoparticles on vascular transport of macromolecules and drugs.

Raw single-wall carbon nanotubes induce oxidative stress and activate MAPKs, AP-1, NF-kappaB, and Akt in normal and malignant human mesothelial cells.

BACKGROUND: Single-wall carbon nanotubes (SWCNTs), with their unique physicochemical and mechanical properties, have many potential new applications in medicine and industry. There has been great concern subsequent to preliminary investigations of the toxicity, biopersistence, pathogenicity, and ability of SWCNTs to translocate to subpleural areas. These results compel studies of potential interactions of SWCNTs with mesothelial cells. OBJECTIVE: Exposure to asbestos is the primary cause of malignant mesothelioma in 80-90% of individuals who develop the disease. Because the mesothelial cells are the primary target cells of asbestos-induced molecular changes mediated through an oxidant-linked mechanism, we used normal mesothelial and malignant mesothelial cells to investigate alterations in molecular signaling in response to a commercially manufactured SWCNT. METHODS: In the present study, we exposed mesothelial cells to SWCNTs and investigated reactive oxygen species (ROS) generation, cell viability, DNA damage, histone H2AX phosphorylation, activation of poly(ADP-ribose) polymerase 1 (PARP-1), stimulation of extracellular signal-regulated kinase (ERKs), Jun N-terminal kinases (JNKs), protein p38, and activation of activator protein-1 (AP-1), nuclear factor kappaB (NF-kappaB), and protein serine-threonine kinase (Akt). RESULTS: Exposure to SWCNTs induced ROS generation, increased cell death, enhanced DNA damage and H2AX phosphorylation, and activated PARP, AP-1, NF-kappaB, p38, and Akt in a dose-dependent manner. These events recapitulate some of the key molecular events involved in mesothelioma development associated with asbestos exposure. CONCLUSIONS: The cellular and molecular findings reported here do suggest that SWCNTs can cause potentially adverse cellular responses in mesothelial cells through activation of molecular signaling associated with oxidative stress, which is of sufficient significance to warrant in vivo animal exposure studies.