Long-Lifespan Fibrous Aqueous Ni//Bi Battery Enabled by Bi2O3-Bi2S3 Hierarchical Heterostructures.

Bismuth oxide (Bi2O3) materials are considered as great promising anodes for aqueous batteries on account of the high capacity as well as wide potential plateau. Nevertheless, the low conductivity and severe volumetric change of Bi2O3 in the course of cycling are the main limiting factors for their application in energy-storage systems. Herein, we propose and design unique hierarchical heterostructures constructed by Bi2O3 and Bi2S3 nanosheets (NSs) manufactured immediately on the surface of carbon nanotube fibers (CNTFs). The Bi2O3-Bi2S3 (BO-BS) exhibits enhanced conductivity and increased stability in comparison with pure Bi2O3 and Bi2S3. The BO-BS NSs/CNTF electrode indicates exceptional rate capability and cycling stability, while creating a high reversible capacity of 0.68 mAh cm-2 at 4 mA cm-2, as anticipated. Additionally, the quasi-solid-state fibrous aqueous Ni//Bi battery that was built with the BO-BS NSs/CNTF anode delivers an exceptional cycling stability of 52.7% capacity retention after 4000 cycles at 80 mA cm-2, an ultrahigh capacity of 0.35 mAh cm-2 at 4 mA cm-2, and a high energy density of 340.1 mWh cm-3 at 880 mW cm-3. This work demonstrates the potential of constructing hierarchical heterostructures of bismuth-based materials for high-performance aqueous Ni//Bi batteries and other energy-storage devices.

Estimating the direction of arrival of spatially spread sources using block-sparse Bayesian learning with an extended dictionary.

Estimating the direction of arrival (DOA) of spatially spread sources is a significant challenge in array signal processing. This work introduces an effective method within the sparse Bayesian framework to tackle this issue. A spatially spread source is modeled using a multi-dimensional Slepian signal subspace that expands the dictionary and results in a block-sparse structured solution. By taking advantage of block-sparse Bayesian learning, parameter estimation becomes feasible. A complex Gaussian posterior is derived under a multi-snapshot block-sparse framework with a complex Gaussian prior and varying noise conditions. The hyperparameters are estimated using the expectation-maximization algorithm. Through numerical tests and sea test data evaluations, the proposed method shows superior energy focusing for spatially spread signals. Under limited snapshots and challenging signal-to-noise ratios, the current method can still offer precise DOA determination for spatially spread sources.

Emerging Amorphous to Crystalline Conversion Chemistry in Ca-Doped VO2 Cathodes for High-Capacity and Long-Term Wearable Aqueous Zinc-Ion Batteries.

Amorphous transition metal oxides have attracted significant attention in energy storage devices owing to their potentially desirable electrochemical properties caused by abundant unsaturated dangling bonds. However, the amorphization further amplifies the shortcoming of the poor intrinsic electronic conductivity of the metal oxides, resulting in unsatisfying rate capability and power density. Herein, freestanding amorphous Ca-doped V2 O5 (a-Ca-V2 O5 ) cathodes are successfully prepared via in situ electrochemical oxidation of Ca-doped VO2 nanoarrays for wearable aqueous zinc-ion batteries. The doping of Ca and construction of freestanding structure effectively uncover the potential of amorphous V2 O5 , which can make full use of the abundant active sites for high volumetric capacity and simultaneously achieve fast reaction kinetics for excellent rate performance. More importantly, the introduction of Ca can notably reduce the formation energy of VO2 according to theoretical calculation results and realizes amorphous to crystalline reversible conversion chemistry in the charge/discharge procedure, thereby facilitating the reversible capacity of the newly developed a-Ca-V2 O5 . This work provides an innovative design strategy to construct high-rate capacity amorphous metal oxides as freestanding electrodes for low-cost and high-safe wearable energy-storage technology.

T-2 toxin-induced testicular impairment by triggering oxidative stress and ferroptosis.

T-2 toxin is a trichothecene mycotoxin of significant danger to humans and animals. Its impact on reproductive toxicity is attributed to oxidative stress, which ultimately leads to cell death. Ferroptosis is a programmed cell death that characterized by lipid peroxidation. This study aimed to investigate the toxic effects of T-2 toxin on mouse testis and the potential mechanism of T-2 toxin-induced ferroptosis. T-2 toxin significantly altered the morphology of the testis and decreased testosterone level, sperm concentration, and increased sperm malformation rate, as well as induced oxidative damage with reactive oxygen species and malondialdehyde accumulated, and activity of superoxide dismutase, glutathione peroxidase decreased. Additionally, T-2 toxin induced ferroptosis by accumulating iron ions, increasing prostaglandin endoperoxide synthase 2, downregulating glutathione peroxidase 4 and ferritin heavy chain 1, as well as manifesting ferroptotic morphological alterations, ultimately leading to testicular impairment. Administration of ferroptosis inhibitor liproxstatin-1 or antioxidant resveratrol effectively mitigated the T-2 toxin-induced ferroptosis and testicular injury. These findings provided novel insights into the fundamental mechanism of T-2 toxin-induced cell death and furnished further proof of the potential therapeutic effect in addressing T-2 toxin-induced testicular impairment.

The phosphoproteome is a first responder in tiered cellular adaptation to chemical stress followed by proteomics and transcriptomics alteration.

Next-generation risk assessment (NGRA) for environmental chemicals involves a weight of evidence (WoE) framework integrating a suite of new approach methodologies (NAMs) based on points of departure (PoD) obtained from in vitro assays. Among existing NAMs, the omic-based technologies are of particular importance based on the premise that any apical endpoint change indicative of impaired health must be underpinned by some alterations at the omics level, such as transcriptome, proteome, metabolome, epigenome and genome. Transcriptomic assay plays a leading role in providing relatively conservative PoDs compared with apical endpoints. However, it is unclear whether and how parameters measured with other omics techniques predict the cellular response to chemical perturbations, especially at exposure levels below the transcriptomically defined PoD. Multi-omics coverage may provide additional sensitive or confirmative biomarkers to complement and reduce the uncertainty in safety decisions made using targeted and transcriptomics assays. In the present study, we conducted multi-omics studies of transcriptomics, proteomics and phosphoproteomics on two prototype compounds, coumarin and 2,4-dichlorophenoxyacetic acid (2,4-D), with multiple chemical concentrations and time points, to understand the sensitivity of the three omics techniques in response to chemically-induced changes in HepG2. We demonstrated that, phosphoproteomics alterations occur not only earlier in time, but also more sensitive to lower concentrations than proteomics and transcriptomics when the HepG2 cells were exposed to various chemical treatments. The phosphoproteomics changes appear to approach maximum when the transcriptomics alterations begin to initiate. Therefore, it is proximal to the very early effects induced by chemical exposure. We concluded that phosphoproteomics can be utilized to provide a more complete coverage of chemical-induced cellular alteration and supplement transcriptomics-based health safety decision making.

T-2 toxin induces cardiotoxicity by activating ferroptosis and inhibiting heme oxygenase-1.

T-2 toxin, a natural secondary sesquiterpenoid metabolite produced by numerous strains of Fusarium fungi, is prevalent in both contaminated food and the environment. T-2 toxin is known to be highly toxic to the cardiovascular system, but the precise mechanisms that lead to T-2 toxin-induced cardiotoxicity are not yet fully understood. Recent findings indicate that ferroptosis is a pivotal factor in cardiovascular damage and exhibits a strong correlation with the detrimental impacts of T-2 toxin. The present study was designed to examine the involvement of ferroptosis in T-2 toxin-induced cardiac injury. Male mice and human cardiomyocytes were subjected to T-2 toxin for 24 h to induce acute cardiotoxicity for in vivo and in vitro studies, respectively. Our results demonstrated that T-2 toxin increased reactive oxygen species production, malondialdehyde, and decreased glutathione/oxidized glutathione and adenosine triphosphate levels. Furthermore, T-2 toxin was observed to activate ferroptosis, as evidenced by an increase in iron (Fe2+) concentration and upregulation of prostaglandin endoperoxide synthase 2, downregulation of glutathione peroxidase 4 and ferritin heavy chain 1, as well as ferroptotic morphological alterations. Inhibition of ferroptosis by Liproxstatin-1 reversed T-2 toxin-induced cardiac injury. Additionally, the downregulation of heme oxgenase-1 (HO-1) expression by T-2 toxin exacerbates ferroptosis and oxidative damage, which can be further aggravated by HO-1 inhibition with Sn-protoporphyrin. These findings provide novel insights into the mechanism of T-2 toxin-induced cardiotoxicity and suggest that targeting ferroptosis and HO-1 may represent a promising cardioprotective strategy against T-2 toxin.

Laser waterless cleaning of residual organic solvents on the surface of polyurethane coatings.

Residual organic solvents have a great impact on the physical and mental health of equipment operators in industry and agriculture. Laser waterless cleaning technology of residual organic solvents on the surface of polyurethane coatings has great application prospects and is a good way to tackle the pollution problem. In this paper, the evolutionary behavior of a laser waterless cleaning mechanism and substrate surface state is analyzed. The influence law of laser energy density and scanning speed on the residual solvent cleaning effect was investigated. The optimal laser cleaning parameters were obtained by comprehensive evaluation of the substrate surface cleaning effect and microscopic morphology. The peak of solvent characteristics before and after laser cleaning was detected by Raman spectroscopy. The results demonstrated that the laser cleaning effect was better with the increase of energy density or the decrease of scanning speed in the substrate damage range, and the best laser cleaning parameters were laser energy density of 0.24J/c m 2 and scanning speed of 500 mm/s. A significant reduction of the peak of Raman spectroscopy was found, reflecting the excellent effect of laser waterless cleaning of residual organic solvents.

Metformin Ameliorates 2.856 GHz Microwave- Radiation-Induced Reproductive Impairments in Male Rats via Inhibition of Oxidative Stress and Apoptosis.

The reproductive system has been increasingly implicated as a sensitive target of microwave radiation. Oxidative stress plays a critical role in microwave radiation -induced reproductive damage, though precise mechanisms are obscure. Metformin, a widely used antidiabetic drug, has emerged as an efficient antioxidant against a variety of oxidative injuries. In the present study, we hypothesized that metformin can function as an antioxidant and protect the reproductive system from microwave radiation. To test this hypothesis, rats were exposed to 2.856 GHz microwave radiation for 6 weeks to simulate real-life exposure to high-frequency microwave radiation. Our results showed that exposure to 2.856 GHz microwave radiation elicited serum hormone disorder, decreased sperm motility, and depleted sperm energy, and it induced abnormalities of testicular structure as well as mitochondrial impairment. Metformin was found to effectively protect the reproductive system against structural and functional impairments caused by microwave radiation. In particular, metformin can ameliorate microwave-radiation-induced oxidative injury and mitigate apoptosis in the testis, as determined by glutathione/-oxidized glutathione (GSH/GSSG), lipid peroxidation, and protein expression of heme oxygenase-1 (HO-1). These findings demonstrated that exposure to 2.856 GHz microwave radiation induces obvious structural and functional impairments of the male reproductive system, and suggested that metformin can function as a promising antioxidant to inhibit microwave-radiation-induced harmful effects by inhibiting oxidative stress and apoptosis.

Free-standing conductive nickel metal-organic framework nanowires as bifunctional electrodes for wearable pressure sensors and Ni-Zn batteries.

Free-standing metal-organic frameworks (MOFs) with controllable structure and good stability are emerging as promising materials for applications in flexible pressure sensors and energy-storage devices. However, the inherent low electrical conductivity of MOF-based materials requires complex preparation processes that involve high-temperature carbonization. This work presents a simple method to grow conductive nickel MOF nanowire arrays on carbon cloth (Ni-CAT@CC) and use Ni-CAT@CC as the functional electrodes for flexible piezoresistive sensor. The resulting sensor is able to monitor human activity, including elbow bending, knee bending, and wrist bending. Besides, the soft-packaged aqueous Ni-Zn battery is assembled with Ni-CAT@CC, a piece of glass microfiber filters, and Zn foil acting as cathode, separator, and anode, respectively. The Ni-Zn battery can be used as a power source for finger pressure monitoring. This work demonstrates free-standing MOF-based nanowires as bifunctional fabric electrodes for wearable electronics.

Effect of flocculant dosage on the settling properties and underflow concentration of thickener for flocculated tailing suspensions.

Flocculation is important in the thickening process to improve the underflow concentration in thickeners for tailing suspensions. Traditional zone settling velocity (ZSV) functions ignore the effect of flocculant dosage on the ZSV and the thickening behavior of thickeners. To investigate the effect of flocculant dosage on the settling flux function, a series of batch settling tests were conducted at various flocculant dosages for unclassified and fine tailings. The correlation among flocculant dosage, solid fraction, and parameters in the ZSV function was revealed. Moreover, a simulation of continuous thickening based on the ZSV function was performed. Results indicated that flocculation influenced settling velocity and floc density. With an increased flocculant dosage, the settling velocity of floc increased, resulting in increased underflow concentration. Conversely, floc density decreased due to a stronger particle-particle interaction, leading to a decreased underflow concentration.

Role of FOXO3a Transcription Factor in the Regulation of Liver Oxidative Injury.

Oxidative stress has been identified as a key mechanism in liver damage caused by various chemicals. The transcription factor FOXO3a has emerged as a critical regulator of redox imbalance. Multiple post-translational changes and epigenetic processes closely regulate the activity of FOXO3a, resulting in synergistic or competing impacts on its subcellular localization, stability, protein-protein interactions, DNA binding affinity, and transcriptional programs. Depending on the chemical nature and subcellular context, the oxidative-stress-mediated activation of FOXO3a can induce multiple transcriptional programs that play crucial roles in oxidative injury to the liver by chemicals. Here, we mainly review the role of FOXO3a in coordinating programs of genes that are essential for cellular homeostasis, with an emphasis on exploring the regulatory mechanisms and potential application of FOXO3a as a therapeutic target to prevent and treat liver oxidative injury.

Vanadium Dioxide Nanosheets Supported on Carbonized Cotton Fabric as Bifunctional Textiles for Flexible Pressure Sensors and Zinc-Ion Batteries.

Flexible pressure sensors and aqueous batteries have been widely used in the rapid development of wearable electronics. The synergistic functionalities of versatile materials with multidimensional architectures are recognized to have a significant impact on the performance of flexible electronics. Herein, a facile hydrothermal strategy was demonstrated to conformally grow vanadium dioxide nanosheets on carbonized cotton fabrics (VO2/CCotton), which is a candidate material used in flexible piezoresistive sensors. As a result, the VO2/CCotton-based pressure sensor behaved with high sensitivity (S = 7.12 kPa-1 in the pressure range of 0-2.0 kPa) and a stable sensing ability in a wide pressure scale of 0-120 kPa. Further practical applications were performed in monitoring delicate physiological signals as well, such as twisting, blowing, and voice vibration recognitions. In addition, another application for energy storage was investigated as well. A quasi-solid-state aqueous zinc-ion battery was assembled with VO2/CCotton as the cathode and a film of Zn nanosheets/carbon nanotube as the anode. A capacity as high as 301.5 mAh g-1 and remarkable durability of 88.7% capacity retention after 5000 cycles at 10 A g-1 were found. These exceptional outcomes are attributed to the unique three-dimensional architecture and the prominent synergetic effects of CCotton and VO2 and allow for the proposal of novel guidelines for next-generation multifunctional flexible electronics.

NRF2/PGC-1α-mediated mitochondrial biogenesis contributes to T-2 toxin-induced toxicity in human neuroblastoma SH-SY5Y cells.

The T-2 toxin is a highly toxic trichothecene mycotoxin that would cause serious toxicity in humans and animals. Recent studies suggest that the central nervous system (CNS) is susceptible to T-2 toxin, which can easily cross the blood-brain barrier, accumulate in brain tissues, and cause neurotoxicity. The growing evidence indicates that oxidative damage and mitochondrial dysfunction play a critical role in T-2 toxin-induced neurotoxicity, but the mechanisms are still poorly understood. Our present study showed that T-2 toxin decreased cell viability and increased lactate dehydrogenase leakage in human neuroblastoma SH-SY5Y cells in a concentration- and time-dependent manner. T-2 toxin elicited prominent oxidative stress and mitochondrial dysfunction, as evidenced by the promotion of cellular reactive oxygen species generation, disruption of the mitochondrial membrane potential, depletion of glutathione and reduction of the cellular ATP content. T-2 toxin impaired mitochondrial biogenesis, including decreased mitochondrial DNA copy number and affected the nuclear factor erythroid 2 related factor 2 (NRF2) / peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α) pathway by upregulating NRF2 mRNA and protein expression while inhibiting the expression of PGC-1α, nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). NRF2 knockdown was found to significantly exacerbate T-2 toxin-induced cytotoxicity, oxidative stress, and mitochondrial dysfunction, as well as aggravate mitochondrial biogenesis impairment. NRF2 knockdown compromised T-2 toxin-induced upregulation of NRF2, but augmented the inhibition of PGC-1α, NRF1, and TFAM by T-2 toxin. Taken together, these findings suggest that T-2 toxin-induced oxidative stress and mitochondrial dysfunction in SH-SY5Y cells, at least in part by, NRF2/PGC-1α pathway-mediated mitochondrial biogenesis.

Dynamic cerebral blood flow changes with FOXOs stimulation are involved in neuronal damage associated with high-altitude cerebral edema in mice.

Acute hypobaric hypoxia (AHH) exposure causes altitude mountain sickness (AMS) and life-threatening high altitude cerebral edema (HACE). Despite decades of research, the role of cerebral blood flow (CBF) changes in the pathophysiology of severe AMS remains unclear. The current study evaluated spatiotemporal responses of CBF associated with HACE in mice during the early stages of ascent to high altitudes. First, mice were exposed to AHH to test their tolerance to increasing altitudes (3000-8000 m). Because of its significant influence on both locomotor activity and rotarod behavior tests in mice, further observations were initiated at an altitude of 6000 m to investigate the specific pathophysiology of AMS. Compared with controls, laser speckle contrast imaging (LSCI) revealed a significant decrease in CBF during the early stage (0.5-24 h) at an altitude of 6000 m that was accompanied by a significant increase in brain water content (BWC). Moreover, observations of brain lipid oxidative damage and oxidative stress during the early stage of AHH exposure revealed DNA and cellular damage in cortical and hippocampal regions. Transcriptome profiling of the hippocampus revealed upregulation of forkhead box transcription factors. Similarly, western blot assays revealed upregulation of FOXO1a, FOXO3a, caspase-3 and Bax, and downregulation of Bcl-2, indicating a temporal influence of AHH on mitochondrial function and neuronal apoptosis. Thus, we found that the pathophysiology of HACE occurred with dynamic CBF changes, which triggered oxidative stress and neuronal damage in the mouse brain after AHH exposure. Our findings provide potential strategies for treatment of AHH in the future.

Synergistic effects of Rapamycin and Fluorouracil to treat a gastric tumor in a PTEN conditional deletion mouse model.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) in PI3K/Akt/mTOR pathway is essential in inhibiting tumor growth and metastasis. However, whether the mutation of PTEN gene could induce tumorigenesis and impact the treatment of gastric cancer is still unclear. The purpose of the study was to investigate the combined treatment of gastric tumorigenesis using Rapamycin and Fluorouracil (5-Fu) through interfering with the Akt/mTOR pathway in a mouse model with PTEN conditional deletion. Three groups of mice were exposed for 5 days to Rapamycin and 5-Fu separately and together. The gene expression of the Akt/mTOR pathway, the protein expression of caspase-3 and p-Akt, p-S6K and p-4EBP1, and the pathological changes in stomachs were analyzed. Our study demonstrates that the conditional PTEN deletion in the cells of glandular stomach induces hyperplastic gastric tumors in mice. The combined Rapamycin administration with 5-Fu resulted in better outcomes than their separate administration for the treatment of gastric cancer by inhibiting the mTOR signal pathway. Our study indicates that Rapamycin has a synergistic interaction with chemotherapeutic 5-Fu, and demonstrates a potential therapeutic combination treatment on glandular stomach tumor with PTEN functional absence or aberrantly activated Akt/mTOR pathway. It provides important insights into the inhibition of the Akt/mTOR pathway in gastric cancer clinical therapy.

NRF2 deficiency sensitizes human keratinocytes to zinc oxide nanoparticles-induced autophagy and cytotoxicity.

Zinc oxide nanoparticles (ZnO NPs) are one of the most commonly used metal oxide particles in many industrial fields. Many studies have shown that ZnO NPs induce harmful effects to human skin, but the mechanisms remain poorly understood. Our results showed that ZnO NPs concentration-dependently induced cytotoxicity, ROS accumulation, and mitochondrial dysfunction in HaCaT cells. The expressions of adaptive antioxidant response transcriptional factor NRF2 and autophagy-related proteins P62 and LC3 II/I were increased by ZnO NPs. Knock-down of NRF2 (NRF2-KD) sensitized the cells to ZnO NPs-induced autophagy and cytotoxicity while an autophagy inhibitor, 3-methyladenine, protected the cells from ZnO NPs-induced cell death. These results demonstrated that NRF2 deficiency sensitizes human keratinocytes to ZnO NPs induced autophagy and cytotoxicity, and proposed a key role of NRF2 in protecting skin cells against ZnO NPs through regulation of antioxidants and autophagy.

Next generation risk assessment (NGRA): Bridging in vitro points-of-departure to human safety assessment using physiologically-based kinetic (PBK) modelling - A case study of doxorubicin with dose metrics considerations.

Using the chemical doxorubicin (DOX), the objective of the present study was to evaluate the impact of dose metrics selection in the new approach method of integrating physiologically-based kinetic (PBK) modelling and relevant human cell-based assays to inform a priori the point of departure for human health risk. We reviewed the literature on the clinical consequences of DOX treatment to identify dosing scenarios with no or mild cardiotoxicity observed. Key concentrations of DOX that induced cardiomyocyte toxicity in vitro were derived from studies of our own and others. A human population-based PBK model of DOX was developed and verified against pharmacokinetic data. The model was then used to predict plasma and extracellular and intracellular heart concentrations of DOX under selected clinical settings and compared with in vitro outcomes, based on several dose metrics: Cmax (maximum concentration) or AUC (area under concentration-time curve) in free or total form of DOX. We found when using in vitro assays to predict cardiotoxicity for DOX, AUC is a better indicator. Our study illustrates that when appropriate dose metrics are used, it is possible to combine PBK modelling with in vitro-derived toxicity information to define margins of safety and predict low-risk human exposure levels.

A highly-sensitive "turn on" probe based on coumarin ß-diketone for hydrazine detection in PBS and living cells.

Herein, a new "turn on" fluorescent probe C-1 is developed to specifically detect hydrazine using coumarin nucleus as the fluorophore and ß-diketone as the recognition group. The probe shows high selectivity towards hydrazine over other common ions and amine-containing species, as well as good water solubility and quantitative detectability of hydrazine in concentration range of 1-200 µM. The detection limit is as low as 1.89 ppb, which is lower than the threshold set by EPA (10 ppb). Probe-coated filter papers are confirmed to detect gaseous hydrazine successfully through obvious fluorescence color changes. In addition, the probe has been verified to detect hydrazine in actual water environment and living cells.

Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes.

BACKGROUND: Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in a variety of fields such as industrial, pharmaceutical, and household applications. Increasing evidence suggests that ZnO NPs could elicit unignorable harmful effect to the cardiovascular system, but the potential deleterious effects to human cardiomyocytes remain to be elucidated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been increasingly used as a promising in vitro model of cardiomyocyte in various fields such as drug cardiac safety evaluation. Herein, the present study was designed to elucidate the cardiac adverse effects of ZnO NPs and explore the possible underlying mechanism using hiPSC-CMs. METHODS: ZnO NPs were characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity induced by ZnO NPs in hiPSC-CMs was evaluated by determination of cell viability and lactate dehydrogenase release. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by high-content analysis (HCA). Mitochondrial biogenesis was assayed by detection of mtDNA copy number and PGC-1α pathway. Moreover, microelectrode array techniques were used to investigate cardiac electrophysiological alterations. RESULTS: We demonstrated that ZnO NPs concentration- and time-dependently elicited cytotoxicity in hiPSC-CMs. The results from HCA revealed that ZnO NPs exposure at low-cytotoxic concentrations significantly promoted ROS generation and induced mitochondrial dysfunction. We further demonstrated that ZnO NPs could impair mitochondrial biogenesis and inhibit PGC-1α pathway. In addition, ZnO NPs at insignificantly cytotoxic concentrations were found to trigger cardiac electrophysiological alterations as evidenced by decreases of beat rate and spike amplitude. CONCLUSION: Our findings unveiled the potential harmful effects of ZnO NPs to human cardiomyocytes that involve mitochondrial biogenesis and the PGC-1α pathway that could affect cardiac electrophysiological function.

Integration of in vitro data from three dimensionally cultured HepaRG cells and physiologically based pharmacokinetic modeling for assessment of acetaminophen hepatotoxicity.

Selection of appropriate fit-for-purpose in vitro and in silico models is critical for non-animal safety assessment of chemical-induced hepatoxicity. The present study evaluated the feasibility of integrating in vitro data from three-dimensionally (3D)-cultured HepaRG cells and physiologically based pharmacokinetic (PBPK) modeling to predict chemical-induced liver toxicity. A 3D organoid culture system was established using an ultralow attachment method. HepaRG cells cultured in a two-dimensional (2D) monolayer and under 3D conditions were exposed to acetaminophen (APAP) at concentrations of 0.16-20 mM. The results showed that the viability of both 3D- and 2D cultured cells was significantly decreased by APAP in a concentration-dependent manner. Furthermore, 3D cultures were more sensitive to APAP-induced mitochondrial damage than 2D cultures were, based on measurements of mitochondrial superoxide accumulation and mitochondrial membrane potential loss. PBPK simulations using nominal in vitro concentrations showed that the APAP concentration eliciting mitochondrial damage was closer to the predicted peak liver concentration in humans in 3D cultures than it was in 2D cultures. In summary, our results suggest that combining in vitro data from 3D HepaRG cultures and PBPK modeling provides a promising tool for assessment of liver injury.