3D Airway Epithelial-Fibroblast Biomimetic Microfluidic Platform to Unravel Engineered Nanoparticle-Induced Acute Stress Responses as Exposome Determinants.

Insights into how biological systems respond to high- and low-dose acute environmental stressors are a fundamental aspect of exposome research. However, studying the impact of low-level environmental exposure in conventional in vitro settings is challenging. This study employed a three-dimensional (3D) biomimetic microfluidic lung-on-chip (µLOC) platform and RNA-sequencing to examine the effects of two model anthropogenic engineered nanoparticles (NPs): zinc oxide nanoparticles (Nano-ZnO) and copier center nanoparticles (Nano-CCP). The airway epithelium exposed to these NPs exhibited dose-dependent increases in cytotoxicity and barrier dysregulation (dominance of the external exposome). Interestingly, even nontoxic and low-level exposure (10 µg/mL) of the epithelium compartment to Nano-ZnO triggered chemotaxis of lung fibroblasts toward the epithelium. An increase in α smooth muscle actin (α-SMA) expression and contractile activity was also observed in these cells, indicating a bystander-like adaptive response (dominance of internal exposome). Further bioinformatics and network analysis showed that a low-dose Nano-ZnO significantly induced a robust transcriptomic response and upregulated several hub genes associated with the development of lung fibrosis. We propose that Nano-ZnO, even at a no observable effect level (NOEL) dose according to conventional standards, can function as a potent nanostressor to disrupt airway epithelium homeostasis. This leads to a cascade of profibrotic events in a cross-tissue compartment fashion. Our findings offer new insights into the early acute events of respiratory harm associated with environmental NPs exposure, paving the way for better exposomic understanding of this emerging class of anthropogenic nanopollutants.

Engineering tumoral vascular leakiness with gold nanoparticles.

Delivering cancer therapeutics to tumors necessitates their escape from the surrounding blood vessels. Tumor vasculatures are not always sufficiently leaky. Herein, we engineer therapeutically competent leakage of therapeutics from tumor vasculature with gold nanoparticles capable of inducing endothelial leakiness (NanoEL). These NanoEL gold nanoparticles activated the loss of endothelial adherens junctions without any perceivable toxicity to the endothelial cells. Microscopically, through real time live animal intravital imaging, we show that NanoEL particles induced leakiness in the tumor vessels walls and improved infiltration into the interstitial space within the tumor. In both primary tumor and secondary micrometastases animal models, we show that pretreatment of tumor vasculature with NanoEL particles before therapeutics administration could completely regress the cancer. Engineering tumoral vasculature leakiness represents a new paradigm in our approach towards increasing tumoral accessibility of anti-cancer therapeutics instead of further increasing their anti-cancer lethality.

Human hair proteins as natural reactive oxygen species scavengers for in vitro applications.

Human hair proteins are recognized for their intrinsically high cysteine content. They can be solubilized while preserving their highly reductive thiol groups for free radical scavenging applications. The presence of aromatic and nucleophilic amino acids such as methionine, serine, phenylalanine, and threonine further contribute to the antioxidative potential of this material. Herein, utilizing the DPPH (2,2-diphenyl-1-picrylhydrazyl) and acellular 2',7'-dichlorodihydrofluorescein diacetate (H2 DCFDA) assays, keratins are demonstrated to possess the highest radical scavenging activity among the studied hair proteins. Consequently, protection against hydrogen peroxide-induced oxidative stress in human dermal fibroblasts (HDFs) cultured in human hair keratin supplemented media is demonstrated. Quenching of reactive oxygen species in the HDF is observed using the CellROX Green dye and the expression levels of antioxidant (HMOX1, SOD2, GPX1) and tumor suppressor (TP53) genes is analyzed using qPCR. Collectively, this study presents further evidence and demonstrates the in vitro application potential of hair proteins, especially keratins, as an antioxidizing supplement.

Nanoparticle-induced chemoresistance: the emerging modulatory effects of engineered nanomaterials on human intestinal cancer cell redox metabolic adaptation.

The widespread use of engineered nanomaterials (ENMs) in food products necessitates the understanding of their impact on the gastrointestinal tract (GIT). Herein, we screened several representative food-borne comparator ENMs (i.e. ZnO, SiO2 and TiO2 nanoparticles (NPs)) and report that human colon cancer cells can insidiously exploit ZnO NP-induced adaptive response to acquire resistance against several chemotherapeutic drugs. By employing a conditioning and challenge treatment regime, we demonstrate that repeated exposure to a non-toxic dose of ZnO NPs (20 µM) could dampen the efficacy of cisplatin, paclitaxel and doxorubicin by 10-50% in monolayer culture and 3D spheroids of human colon adenocarcinoma cells. Structure-activity relationship studies revealed a complex interplay between nanoparticle surface chemistry and cell type in determining the chemoresistance-inducing effect, with silica coated ZnO NPs having a negligible influence on the anticancer treatment. Mechanistically, we showed that the pro-survival paracrine signaling was potentiated and propagated by a subset of ZnO NP "stressed" (Zn2++/ROS+) cells to the surrounding "bystander" (Zn2++/ROS-) cells. Transcriptome profiling, bioinformatics analysis and siRNA gene knockdown experiments revealed the nuclear factor erythroid 2-related factor 2 (Nrf2) as the key modulator of the ZnO NP-induced drug resistance. Our findings suggest that a ROS-inducing ENM can emerge as a nano-stressor, capable of regulating the chemosensitivity of colon cancer cells.

Association of nanoparticle exposure with serum metabolic disorders of healthy adults in printing centers.

Printers are everyday devices in both our homes and workplaces. We have previously found high occupational exposure levels to toner-based printer emitted nanoparticles (PEPs) at printing centers. To elucidate the potential health effects from exposure to PEPs, a total of 124 human serum samples were collected from 32 workers in the printing centers during the repeated follow-up measurements, and global serum metabolomics were analyzed in three ways: correlation between metabolic response and personal exposure (dose response exposure); metabolite response changes between Monday and Friday of a work week (short-term exposure), and metabolite response in relation to length of service in a center (long-term exposure). A total of 52 key metabolites changed significantly in relation to nanoparticle exposure levels. The primary dysregulated pathways included inflammation and immunity related arginine and tryptophan metabolism. Besides, some distinct metabolite expression patterns were found to occur during the transition from short-term to long-term exposures, suggesting cumulative effect of PEPs exposure. These findings, for the first time, highlight the inhalation exposure responses to printer emitted nanoparticles at the metabolite level, potentially serving as pre-requisites for whole organism and population responses, and are inline with emerging findings on potential health effects.

Anisotropic hair keratin-dopamine composite scaffolds exhibit strain-stiffening properties.

Human hair keratin (HHK) has been successfully explored as raw materials for three-dimensional scaffolds for soft tissue regeneration due to its excellent biocompatibility and bioactivity. However, none of the reported HHK based scaffolds is able to replicate the strain-stiffening capacity of living tissues when responding to large deformations. In the present study, strain-stiffening property was achieved in scaffolds fabricated from HHK via a synergistic effect of well-defined, aligned microstructure and chemical crosslinking. Directed ice-templating method was used to fabricate HHK-based scaffolds with highly aligned (anisotropic) microstructure while oxidized dopamine (ODA) was used to crosslink covalently to HHKs. The resultant HHK-ODA scaffolds exhibited strain-stiffening behavior characterized by the increased gradient of the stress-strain curve after the yield point. Both ultimate tensile strength and the elongation at break were enhanced significantly (~700 kPa, ~170%) in comparison to that of HHK scaffolds lacking of aligned microstructure or ODA crosslinking. In vitro cell culture studies indicated that HHK-ODA scaffolds successfully supported human dermal fibroblasts (HDFs) adhesion, spreading and proliferation. Moreover, anisotropic HHK-ODA scaffolds guided cell growth in alignment with the defined microstructure as shown by the highly organized cytoskeletal networks and nuclei distribution. The findings suggest that HHK-ODA scaffolds, with strain-stiffening properties, biocompatibility and bioactivity, have the potential to be applied as biomimetic matrices for soft tissue regeneration.

Biomarkers of oxidative stress in urine and plasma of operators at six Singapore printing centers and their association with several metrics of printer-emitted nanoparticle exposures.

Inhalation of nanoparticles emitted from toner-based printing equipment (TPE), such as laser printers and photocopiers, also known as PEPs, has been associated with systemic inflammation, hypertension, cardiovascular disease, respiratory disorders, and genotoxicity. Global serum metabolomics analysis in 19 healthy TPE operators found 52 dysregulated biomolecules involved in upregulation of inflammation, immune, and antioxidant responses and downregulation of cellular energetics and cell proliferation. Here, we build on the metabolomics study by investigating the association of a panel of nine urinary OS biomarkers reflecting DNA/RNA damage (8OHdG, 8OHG, and 5OHMeU), protein/amino acid oxidation (o-tyrosine, 3-chlorotyrosine, and 3-nitrotyrosine), and lipid oxidation (8-isoprostane, 4-hydroxy nonenal, and malondialdehyde [MDA]), as well as plasma total MDA and total protein carbonyl (TPC), with several nanoparticle exposure metrics in the same 19 healthy TPE operators. Plasma total MDA, urinary 5OHMeU, 3-chlorotyrosine, and 3-nitrotyrosine were positively, whereas o-tyrosine inversely and statistically significantly associated with PEPs exposure in multivariate models, after adjusting for age and urinary creatinine. Urinary 8OHdG, 8OHG, 5OHMeU, and total MDA in urine and plasma had group mean values higher than expected in healthy controls without PEPs exposure and comparable to those of workers experiencing low to moderate levels of oxidative stress (OS). The highest exposure group had OS biomarker values, most notably 8OHdG, 8OHG, and total MDA, that compared to workers exposed to welding fumes and titanium dioxide. Particle number concentration was the most sensitive and robust exposure metric. A combination of nanoparticle number concentration and OS potential of fresh aerosols is recommended for larger scale future studies.

Chronic upper airway and systemic inflammation from copier emitted particles in healthy operators at six Singaporean workplaces.

Toner-based printing equipment (TPE), including laser printers and photocopiers, utilize several engineered nanomaterials (ENMs) to improve toner performance. Operation of TPE, which rarely employ any exposure controls, generates high exposures to nanoparticles that contain ENMs and complex organics. Epidemiological literature in copier operators documents respiratory effects, including nasal blockage, cough, excessive sputum, and breathing difficulties, cardiovascular effects, oxidative stress, and inflammation. However, epidemiological studies in humans with adequate exposure assessment and dose-response analysis are lacking. We present herein the analysis of the upper airway and systemic inflammation in plasma of 19 healthy copier operators at six Singapore workplaces. We employed a repeated panel design (four biomarker measurements over two weeks) combined with a multi-marker approach (14 inflammatory cytokines in plasma and nasal lavage (NL)), and comprehensive exposure assessment using four distinct exposure metrics. We investigated spatial and temporal patterns of markers of upper airway and systemic inflammation and their association with various exposure metrics. Several inflammatory markers, namely fractalkine, IL-1ß, and IL-1α in NL, and fractalkine, IL-1ß, TNF-α, and IFN-γ in plasma, were strongly and positively associated with at least one exposure metric, whereas GM-CSF was negatively associated. The inflammation score was also strongly associated with TPE nanoparticle exposures. Exposure to TPE emissions induced moderate upper airway inflammation and stronger systemic inflammation in these healthy operators, characterized by upregulation of at least IL-1ß, fractalkine, TNF-α and IFN-γ. Proinflammatory cytokines TNF-α, IFN-γ and IL-1ß play an important role in orchestrating inflammatory responses in various clinical conditions, including cardiovascular and autoimmune disease, and likely trigger activation of endothelial cells, leading to overexpression of fractalkine, a chemokine that is involved in and associated with multiple disorders, including atherosclerosis and vascular disease. Future larger-scale epidemiological studies in these workers and consumers exposed chronically to TPE nanoparticle emissions and proactive interventions to reduce or eliminate TPE exposures are recommended.

Characterization of Anisotropic Human Hair Keratin Scaffolds Fabricated via Directed Ice Templating.

Human hair keratin (HHK) is successfully exploited as raw materials for 3D scaffolds for soft tissue regeneration owing to its excellent biocompatibility and bioactivity. However, most HHK scaffolds are not able to achieve the anisotropic mechanical properties of soft tissues such as tendons and ligaments due to lack of tunable, well-defined microstructures. In this study, directed ice templating method is used to fabricate anisotropic HHK scaffolds that are characterized by aligned pores (channels) in between keratin layers in the longitudinal plane. In contrast, pores in the transverse plane maintain a homogenous rounded morphology. Channel widths throughout the scaffolds range from ≈5 to ≈15 µm and are tunable by varying the freezing temperature. In comparison with HHK scaffolds with random, isotropic pore structures, the tensile strength of anisotropic HHK scaffolds is enhanced significantly by up to fourfolds (≈200 to ≈800 kPa) when the tensile load is applied in the direction parallel to the aligned pores. In vitro results demonstrate that the anisotropic HHK scaffolds are able to support human dermal fibroblast adhesion, spreading, and proliferation. The findings suggest that HHK scaffolds with well-defined, aligned microstructure hold promise as templates for soft tissues regeneration by mimicking their anisotropic properties.

Self-Assembly of Solubilized Human Hair Keratins.

Human hair keratins have proven to be a viable biomaterial for diverse regenerative applications. However, the most significant characteristic of this material, the ability to self-assemble into nanoscale intermediate filaments, has not been exploited. Herein, we successfully demonstrated the induction of hair-extracted keratin self-assembly in vitro to form dense, homogeneous, and continuous nanofibrous networks. These networks remain hydrolytically stable in vitro for up to 5 days in complete cell culture media and are compatible with primary human dermal fibroblasts and keratinocytes. These results enhance the versatility of human hair keratins for applications where structured assembly is of benefit.

A high-throughput method to characterize the gut bacteria growth upon engineered nanomaterial treatment.

Human are increasingly exposed to various types of engineered nanomaterials (ENMs) via dietary ingestion of nano-enabled food products, but these ENMs' impact on the gut bacteria health is still poorly understood. Current efforts in understanding the impact of these ENMs are hampered by their optical interferences in conventional quantification and viability assays, such as optical density and whole cell fluorescence staining assays. Therefore, there is a need to develop a more reliable bacteria quantification method in the presence of ENMs to effectively screen the potential adverse effects arising from the exposure of increasing ENMs on human gut microbiome. In this study, we developed a DNA-based quantification (DBQ) method in a 96-well plate format. Post-spiking method was used to correct the interference from ENMs on the reading. We showed the applicability of this method for several types of ENMs, i.e., cellulose nanofiber (CNF), graphene oxide (GO), silicon dioxide (SiO2), and chitosan, both in pure bacterial culture and in vitro human gut microbiome community. The detection limit for the highest dosing of CNF, GO, SiO2, and chitosan ENMs was approximately 0.18, 0.19, 0.05, and 0.24 as OD600, respectively. The method was also validated by a dose response experiment of E. coli with chitosan in the course of 8 hr. We believe that this method has great potential to be used in screening the effect of ENMs on the growth of gut bacteria or any other in vitro models and normalization for metabolites or proteins analysis.

Composite Hydrogels in Three-Dimensional in vitro Models.

3-dimensional (3D) in vitro models were developed in order to mimic the complexity of real organ/tissue in a dish. They offer new possibilities to model biological processes in more physiologically relevant ways which can be applied to a myriad of applications including drug development, toxicity screening and regenerative medicine. Hydrogels are the most relevant tissue-like matrices to support the development of 3D in vitro models since they are in many ways akin to the native extracellular matrix (ECM). For the purpose of further improving matrix relevance or to impart specific functionalities, composite hydrogels have attracted increasing attention. These could incorporate drugs to control cell fates, additional ECM elements to improve mechanical properties, biomolecules to improve biological activities or any combinations of the above. In this Review, recent developments in using composite hydrogels laden with cells as biomimetic tissue- or organ-like constructs, and as matrices for multi-cell type organoid cultures are highlighted. The latest composite hydrogel systems that contain nanomaterials, biological factors, and combinations of biopolymers (e.g., proteins and polysaccharide), such as Interpenetrating Networks (IPNs) and Soft Network Composites (SNCs) are also presented. While promising, challenges remain. These will be discussed in light of future perspectives toward encompassing diverse composite hydrogel platforms for an improved organ environment in vitro.

Transformation of Nanomaterials and Its Implications in Gut Nanotoxicology.

Ingestion of engineered nanomaterials (ENMs) is inevitable due to their widespread utilization in the agrifood industry. Safety evaluation has become pivotal to identify the consequences on human health of exposure to these ingested ENMs. Much of the current understanding of nanotoxicology in the gastrointestinal tract (GIT) is derived from studies utilizing pristine ENMs. In reality, agrifood ENMs interact with their microenvironment, and undergo multiple physicochemical transformations, such as aggregation/agglomeration, dissolution, speciation change, and surface characteristics alteration, across their life cycle from synthesis to consumption. This work sieves out the implications of ENM transformations on their behavior, stability, and reactivity in food and product matrices and through the GIT, in relation to measured toxicological profiles. In particular, a strong emphasis is given to understand the mechanisms through which these transformations can affect ENM induced gut nanotoxicity.

Inflammation Increases Susceptibility of Human Small Airway Epithelial Cells to Pneumonic Nanotoxicity.

Exposure to inhaled anthropogenic nanomaterials (NM) with dimension <100 nm has been implicated in numerous adverse respiratory outcomes. Although studies have identified key NM physiochemical determinants of pneumonic nanotoxicity, the complex interactive and cumulative effects of NM exposure, especially in individuals with preexisting inflammatory respiratory diseases, remain unclear. Herein, the susceptibility of primary human small airway epithelial cells (SAEC) exposed to a panel of reference NM, namely, CuO, ZnO, mild steel welding fume (MSWF), and nanofractions of copier center particles (Nano-CCP), is examined in normal and tumor necrosis factor alpha (TNF-α)-induced inflamed SAEC. Compared to normal SAEC, inflamed cells display an increased susceptibility to NM-induced cytotoxicity by 15-70% due to a higher basal level of intracellular reactive oxygen species (ROS). Among the NM screened, ZnO, CuO, and Nano-CCP are observed to trigger an overcompensatory response in normal SAEC, resulting in an increased tolerance against subsequent oxidative insults. However, the inflamed SAEC fails to adapt to the NM exposure due to an impaired nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated cytoprotective response. The findings reveal that susceptibility to pulmonary nanotoxicity is highly dependent on the interplay between NM properties and inflammation of the alveolar milieu.

Pilot deep RNA sequencing of worker blood samples from Singapore printing industry for occupational risk assessment.

Several engineered nanomaterials (ENMs) are used in toner-based printing equipment (TPE) including laser printers and photocopiers to improve toner performance. High concentration of airborne nanoparticles due to TPE emissions has been documented in copy centers and chamber studies. Recent animal inhalation studies by our group suggested exposure to laser printer-emitted nanoparticles (PEPs) increased cardiovascular risk by impairing ventricular performance and inducing hypertension and arrhythmia, consistent with global transcriptomic and metabolomic profiling results. There has been no genome-wide transcriptomic analysis of workers exposed to TPE emissions to systematically assess the occupational exposure health risks. In this pilot study, deep RNA sequencing of blood samples of workers in two printing companies in Singapore was performed. The genome-scale analysis of the blood samples from TPE exposed workers revealed perturbed transcriptional activities related to inflammatory and immune responses, metabolism, cardiovascular impairment, neurological diseases, oxidative stress, physical morphogenesis/deformation, and cancer, when compared with the control peers (office workers). Many of these disease risks associated with particle inhalation exposures in such work environments were consistent with the observation from the PEPs rat inhalation studies. In particular, the cell adhesion molecules (CAMs) was a top significantly perturbed pathway in blood samples from exposed workers compared with the office workers in both companies. The protein expression of sICAM was verified in plasma of exposed workers, showing a positive correlation with daily average nanoparticle concentration in indoor air measured in these two companies. Larger scale genomic and molecular epidemiology studies in copier operators are warranted in order to assess potential risks from such particulate matter exposures.

Angiopoietin-1 accelerates restoration of endothelial cell barrier integrity from nanoparticle-induced leakiness.

Nanoparticles (NPs) have been widely used in biomedical field for therapeutic treatments, drug carriers, and bio-imaging agent. Recent studies have highlighted the possibility of utilizing inorganic NPs in inducing endothelial leakiness through endothelial remodeling to promote drug transport across the barrier. However, an uncontrolled and persistent leakiness could lead to promiscuous transport of molecules and cells across the barrier, highlighting the pressing need to control the timely recovery from endothelial cell leakiness. Herein, we show that angiopoietin-1 (Ang1) could promote recovery of human microvascular endothelial cells (HMVECs) from titanium dioxide nanoparticle (TiO2 NPs)-induced endothelial leakiness. Ang1 is known as an anti-permeability growth factor which forms complexes with its receptor Tie2 at the cell-to-cell junctions. We find that the introduction of Ang1 not only accelerates the recovery of NP-induced endothelial leakiness (NanoEL) but also promotes cell rigidity by increasing tubulin acetylation, thereby remodels the endothelial cells to further mitigate the effects of NP exposure through the activation of the Akt pathway. Using in vitro metastasis model, we further show that HMVECs treated with TiO2 NPs followed by Ang1 could reduce migration of human skin cancer A431 cells across the endothelial barrier. In summary, Ang1 plays important roles in promoting the recovery of endothelial cell leakiness and endothelial stability through a mechano-transduction pathway and shows great potential as key modulator that allows material scientist to regulate endothelial leakiness induced by NPs.

Nanoparticles promote in vivo breast cancer cell intravasation and extravasation by inducing endothelial leakiness.

While most cancer nanomedicine is designed to eliminate cancer, the nanomaterial per se can lead to the formation of micrometre-sized gaps in the blood vessel endothelial walls. Nanomaterials-induced endothelial leakiness (NanoEL) might favour intravasation of surviving cancer cells into the surrounding vasculature and subsequently extravasation, accelerating metastasis. Here, we show that nanoparticles induce endothelial leakiness through disruption of the VE-cadherin-VE-cadherin homophilic interactions at the adherens junction. We show that intravenously injected titanium dioxide, silica and gold nanoparticles significantly accelerate both intravasation and extravasation of breast cancer cells in animal models, increasing the extent of existing metastasis and promoting the appearance of new metastatic sites. Our results add to the understanding of the behaviour of nanoparticles in complex biological systems. The potential for NanoEL needs to be taken into consideration when designing future nanomedicines, especially nanomedicine to treat cancer.

Inhaled nanomaterials and the respiratory microbiome: clinical, immunological and toxicological perspectives.

Our development and usage of engineered nanomaterials has grown exponentially despite concerns about their unfavourable cardiorespiratory consequence, one that parallels ambient ultrafine particle exposure from vehicle emissions. Most research in the field has so far focused on airway inflammation in response to nanoparticle inhalation, however, little is known about nanoparticle-microbiome interaction in the human airway and the environment. Emerging evidence illustrates that the airway, even in its healthy state, is not sterile. The resident human airway microbiome is further altered in chronic inflammatory respiratory disease however little is known about the impact of nanoparticle inhalation on this airway microbiome. The composition of the airway microbiome, which is involved in the development and progression of respiratory disease is dynamic, adding further complexity to understanding microbiota-host interaction in the lung, particularly in the context of nanoparticle exposure. This article reviews the size-dependent properties of nanomaterials, their body deposition after inhalation and factors that influence their fate. We evaluate what is currently known about nanoparticle-microbiome interactions in the human airway and summarise the known clinical, immunological and toxicological consequences of this relationship. While associations between inhaled ambient ultrafine particles and host immune-inflammatory response are known, the airway and environmental microbiomes likely act as intermediaries and facilitate individual susceptibility to inhaled nanoparticles and toxicants. Characterising the precise interaction between the environment and airway microbiomes, inhaled nanoparticles and the host immune system is therefore critical and will provide insight into mechanisms promoting nanoparticle induced airway damage.

Inorganic Nanomaterials as Highly Efficient Inhibitors of Cellular Hepatic Fibrosis.

Chronic liver dysfunction usually begins with hepatic fibrosis. To date, no effective anti-fibrotic drugs have been approved for clinical use in humans. In the current work, titanium dioxide (TiO2) nanoparticles (NPs) and silicon dioxide (SiO2) NPs are used as active inhibitors with intrinsic chemico-physico properties to block fibrosis and the associated phenotypes through acting on hepatic stellate cells (HSCs, the liver machinery for depositing scar tissues seen in fibrosis). Using LX-2 cells as the HSC model, internalized nanomaterials are found to suppress classical outcomes of cellular fibrosis, for example, inhibiting the expression of collagen I (Col-I) and alpha smooth muscle actin (α-SMA), initiated by transforming growth factor ß (TGF-ß)-activated HSCs in both a concentration-dependent and a time-dependent manner. Biochemically, these nanomaterials could also facilitate the proteolytic breakdown of collagen by up-regulation of matrix metalloproteinases (MMPs) and down-regulation of tissue inhibitors of MMPs (TIMPs). Furthermore, through regulating epithelial-mesenchymal transition (EMT) genes [e.g., E-cadherin (E-Cad) and N-cadherin (N-Cad)], the adhesion and migration profiles of TGF-ß-activated LX-2 cells treated with nanomaterials were further inhibited, reverting them to a more quiescent state. Thus, the collective results pave the new way that nanomaterials can be used as potential therapeutic inhibitors for the treatment of in vivo fibrosis.

Nano-TiO2 Drives Epithelial-Mesenchymal Transition in Intestinal Epithelial Cancer Cells.

The majority of cancer mortality is associated with cancer metastasis. Epithelial-to-mesenchymal transition (EMT) is a process by which cells attain migratory and invasive properties, eventually leading to cancer metastasis. Here, it is shown that titanium dioxide nanoparticles (nano-TiO2 ), a common food additive, can induce the EMT process in colorectal cancer cells. Nano-TiO2 exposure is observed to activate transforming growth factor-ß (TGF-ß)/mitogen-activated protein kinase (MAPK) and wingless (Wnt) pathways, and drive the EMT process. Similarly, silica nanoparticles (nano-SiO2 ) and hydroxyapatite nanoparticles (nano-HA), as food-based additives, can be ingested and accumulated in the stomach, and are found to be able to induce the EMT progression. The implication of this work can be profound for colorectal cancer patients where these food additives may unknowingly and unnecessarily hasten the progression of their cancers.