The cellular protein quality control (PQC) system ensures the intracellular misfolded/unfolded pr... more The cellular protein quality control (PQC) system ensures the intracellular misfolded/unfolded proteins to be detected and eliminated. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the key mechanisms of PQC, which maintain protein homeostasis and ensure cell survival. Here, we show that after internalization by human epithelial cells, gold (Au) nanoparticles (NPs) localized in endoplasmic reticulum (ER) and induced an accumulation of misfolded/unfolded proteins. Au NPs activated UPR, but suppressed ERAD shown by a reduced degradation rate of the ERAD marker CD3-δ-YFP, which triggered ER stress through IRE1-XBP1-Chaperones and PERK-eIF2α-ATF4-CHOP pathways. The Au NP-dependent ER stress consequently induced the intracellular accumulation of ROS, and caused cell apoptosis/death, concomitant to production/release of inflammatory cytokines and chemokines. This study for the first time shows that NPs can interfere with the cellular PQC system by impairing ERAD ...
This study aimed to conduct an integrated and probabilistic risk assessment of gold nanoparticles... more This study aimed to conduct an integrated and probabilistic risk assessment of gold nanoparticles (AuNPs) based on recently published in vitro and in vivo toxicity studies coupled to a physiologically based pharmacokinetic (PBPK) model. Dose-response relationships were characterized based on cell viability assays in various human cell types. A previously well-validated human PBPK model for AuNPs was applied to quantify internal concentrations in liver, kidney, skin, and venous plasma. By applying a Bayesian-based probabilistic risk assessment approach incorporating Monte Carlo simulation, probable human cell death fractions were characterized. Additionally, we implemented in vitro to in vivo and animal-to-human extrapolation approaches to independently estimate external exposure levels of AuNPs that cause minimal toxicity. Our results suggest that under the highest dosing level employed in existing animal studies (worst-case scenario), AuNPs coated with branched polyethylenimine (BP...
This article discusses the risks associated with nanomaterials. The use of nanomaterials in consu... more This article discusses the risks associated with nanomaterials. The use of nanomaterials in consumer products and industrial applications is becoming more prevalent owing to their range of benefits. Nanomaterials have found uses in energy production, home appliances, water treatment, novel therapeutic delivery techniques and dietary supplements, consumer electronics, and sports equipment. While considerable attention has been given to the likely commercial advantages associated with nanomaterials, less emphasis has been placed on the development of a systematic approach for characterizing the human health and environmental risks from exposure to nanomaterials. This article first considers the use of nanomaterials in consumer products and the characterization of nanomaterials before describing a systematic evaluation of the hazards associated with nanomaterials. It also examines pulmonary exposure assessment and dermal exposure assessment, along with risk assessment for exposure to nanomaterials. Finally, it outlines research priorities for the development of more refined estimates of nanomaterial risk.
International Journal of Applied Ceramic Technology, 2007
Three‐dimensional microneedle devices were created by femtosecond laser two photon polymerization... more Three‐dimensional microneedle devices were created by femtosecond laser two photon polymerization (2PP) of organically modified ceramic (Ormocer®) hybrid materials. Arrays of in‐plane and out‐of‐plane hollow microneedles (microneedle length=800 μm, microneedle base diameter=150–300 μm) with various aspect ratios were fabricated. The fracture and penetration properties of the microneedle arrays were examined using compression load testing. In these studies, the microneedle arrays penetrated cadaveric porcine adipose tissue without fracture. Human epidermal keratinocyte viability on the Ormocer® surfaces polymerized using 2PP was similar to that on control surfaces. These results suggest that 2PP is able to create microneedle structures for transdermal drug delivery with a larger range of geometries than conventional microfabrication techniques.
Su1fur mustard BIS(2-CHLOROETHYL) SULFIDE, HD is an alkylating agent that causes severe cutaneous... more Su1fur mustard BIS(2-CHLOROETHYL) SULFIDE, HD is an alkylating agent that causes severe cutaneous injury. The isolated perfused porcine skin flap (IPPSF) is an in vitro model that has been utilized in cutaneous toxicity research. The objective of this study was to characterize the local IPPSF inflammatory response after topical exposure to 5.0 and 10.0 mg/ml of I (n = 5/treatment, n = 5/control). Biochemical markers of viability CUMULATIVE GLUCOSE UTILIZATION (CGU), vascular resistance (VR), morphological parameters, and venous flux of prostaglandin E2 (PGE2), prostaglandin F2% (PGF2%, and interleukin la (IL la)) were determined. HD caused a dose-related response in the formation of gross blisters, and epidermal-dermal separation. Decreases in CGU and an increase in VR were seen in all HD-treated IPPsFs. Increase of both PGE2 and PGF2a was observed only in 5.0 mg/ml HD treatment, which showed the greatest increase in VR, while the 10.0 mg/nil concentration of HD enhanced the release of IL-1a. These results suggest that HD is a potent dermal toxic agent that induces alterations in glucose metabolism and vascular resistance, which resulted in dose-specific patterns of PGE2, PGF2a and IL-la release.
The cellular protein quality control (PQC) system ensures the intracellular misfolded/unfolded pr... more The cellular protein quality control (PQC) system ensures the intracellular misfolded/unfolded proteins to be detected and eliminated. ER-associated degradation (ERAD) and unfolded protein response (UPR) are the key mechanisms of PQC, which maintain protein homeostasis and ensure cell survival. Here, we show that after internalization by human epithelial cells, gold (Au) nanoparticles (NPs) localized in endoplasmic reticulum (ER) and induced an accumulation of misfolded/unfolded proteins. Au NPs activated UPR, but suppressed ERAD shown by a reduced degradation rate of the ERAD marker CD3-δ-YFP, which triggered ER stress through IRE1-XBP1-Chaperones and PERK-eIF2α-ATF4-CHOP pathways. The Au NP-dependent ER stress consequently induced the intracellular accumulation of ROS, and caused cell apoptosis/death, concomitant to production/release of inflammatory cytokines and chemokines. This study for the first time shows that NPs can interfere with the cellular PQC system by impairing ERAD ...
This study aimed to conduct an integrated and probabilistic risk assessment of gold nanoparticles... more This study aimed to conduct an integrated and probabilistic risk assessment of gold nanoparticles (AuNPs) based on recently published in vitro and in vivo toxicity studies coupled to a physiologically based pharmacokinetic (PBPK) model. Dose-response relationships were characterized based on cell viability assays in various human cell types. A previously well-validated human PBPK model for AuNPs was applied to quantify internal concentrations in liver, kidney, skin, and venous plasma. By applying a Bayesian-based probabilistic risk assessment approach incorporating Monte Carlo simulation, probable human cell death fractions were characterized. Additionally, we implemented in vitro to in vivo and animal-to-human extrapolation approaches to independently estimate external exposure levels of AuNPs that cause minimal toxicity. Our results suggest that under the highest dosing level employed in existing animal studies (worst-case scenario), AuNPs coated with branched polyethylenimine (BP...
This article discusses the risks associated with nanomaterials. The use of nanomaterials in consu... more This article discusses the risks associated with nanomaterials. The use of nanomaterials in consumer products and industrial applications is becoming more prevalent owing to their range of benefits. Nanomaterials have found uses in energy production, home appliances, water treatment, novel therapeutic delivery techniques and dietary supplements, consumer electronics, and sports equipment. While considerable attention has been given to the likely commercial advantages associated with nanomaterials, less emphasis has been placed on the development of a systematic approach for characterizing the human health and environmental risks from exposure to nanomaterials. This article first considers the use of nanomaterials in consumer products and the characterization of nanomaterials before describing a systematic evaluation of the hazards associated with nanomaterials. It also examines pulmonary exposure assessment and dermal exposure assessment, along with risk assessment for exposure to nanomaterials. Finally, it outlines research priorities for the development of more refined estimates of nanomaterial risk.
International Journal of Applied Ceramic Technology, 2007
Three‐dimensional microneedle devices were created by femtosecond laser two photon polymerization... more Three‐dimensional microneedle devices were created by femtosecond laser two photon polymerization (2PP) of organically modified ceramic (Ormocer®) hybrid materials. Arrays of in‐plane and out‐of‐plane hollow microneedles (microneedle length=800 μm, microneedle base diameter=150–300 μm) with various aspect ratios were fabricated. The fracture and penetration properties of the microneedle arrays were examined using compression load testing. In these studies, the microneedle arrays penetrated cadaveric porcine adipose tissue without fracture. Human epidermal keratinocyte viability on the Ormocer® surfaces polymerized using 2PP was similar to that on control surfaces. These results suggest that 2PP is able to create microneedle structures for transdermal drug delivery with a larger range of geometries than conventional microfabrication techniques.
Su1fur mustard BIS(2-CHLOROETHYL) SULFIDE, HD is an alkylating agent that causes severe cutaneous... more Su1fur mustard BIS(2-CHLOROETHYL) SULFIDE, HD is an alkylating agent that causes severe cutaneous injury. The isolated perfused porcine skin flap (IPPSF) is an in vitro model that has been utilized in cutaneous toxicity research. The objective of this study was to characterize the local IPPSF inflammatory response after topical exposure to 5.0 and 10.0 mg/ml of I (n = 5/treatment, n = 5/control). Biochemical markers of viability CUMULATIVE GLUCOSE UTILIZATION (CGU), vascular resistance (VR), morphological parameters, and venous flux of prostaglandin E2 (PGE2), prostaglandin F2% (PGF2%, and interleukin la (IL la)) were determined. HD caused a dose-related response in the formation of gross blisters, and epidermal-dermal separation. Decreases in CGU and an increase in VR were seen in all HD-treated IPPsFs. Increase of both PGE2 and PGF2a was observed only in 5.0 mg/ml HD treatment, which showed the greatest increase in VR, while the 10.0 mg/nil concentration of HD enhanced the release of IL-1a. These results suggest that HD is a potent dermal toxic agent that induces alterations in glucose metabolism and vascular resistance, which resulted in dose-specific patterns of PGE2, PGF2a and IL-la release.
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