Construction of a pumpless gravity-driven vascularized Skin-on-a-Chip for the study of hepatocytotoxicity in percutaneous exposure to exogenous chemicals.

The utilization of existing Skin-on-a-Chip (SoC) is constrained by the complex structures, the multiplicity of auxiliary devices, and the inability to evaluate exogenous chemicals that are hepatotoxic after percutaneous metabolism. In this study, a gravity-driven SoC without any auxiliary devices was constructed for the hepatocytotoxicity study of exogenous chemicals. The SoC possesses 3 layers of culture chambers, from top to bottom, for human skin equivalent (HSE), Human Umbilical Vein Endothelial Cells (HUVEC) and hepatocytes (HepG2), and the maintenance and expression capacity of the corresponding cells on the SoC were verified by specificity parameters. The reactivity of the SoC to exogenous chemicals was verified by 2-aminofluorene (2-AF). The SoC can realistically simulate the in vivo exposure process of exogenous chemicals that are percutaneously exposed and metabolized into the bloodstream and then to the liver to produce toxicity, and it can achieve the same effects on transcriptome as those of animal tests at lower exposure levels while examining multiple toxicological targets of the skin, vascular endothelial cells, and hepatocytes. Both in terms of species similarity, the principles of reduction, replacement and refinement (3R), or the level of exposure suggest that the present SoC has a degree of replacement for animal models in assessing exogenous chemicals, especially those that are hepatotoxic after percutaneous metabolism.

ROCK inhibition enhanced hepatocyte liver engraftment by retaining membrane CD59 and attenuating complement activation.

Hepatocyte transplantation can be an effective treatment for patients with certain liver-based metabolic disorders and liver injuries. Hepatocytes are usually infused into the portal vein, from which hepatocytes migrate into the liver and integrate into the liver parenchyma. However, early cell loss and poor liver engraftment represent major hurdles to sustaining the recovery of diseased livers after transplantation. In the present study, we found that ROCK (Rho-associated kinase) inhibitors significantly enhanced in vivo hepatocyte engraftment. Mechanistic studies suggested that the isolation of hepatocytes caused substantial degradation of cell membrane proteins, including the complement inhibitor CD59, probably due to shear stress-induced endocytosis. ROCK inhibition by ripasudil, a clinically used ROCK inhibitor, can protect transplanted hepatocytes by retaining cell membrane CD59 and blocking the formation of the membrane attack complex. Knockdown of CD59 in hepatocytes eliminates ROCK inhibition-enhanced hepatocyte engraftment. Ripasudil can accelerate liver repopulation of fumarylacetoacetate hydrolase-deficient mice. Our work reveals a mechanism underlying hepatocyte loss after transplantation and provides immediate strategies to enhance hepatocyte engraftment by inhibiting ROCK.

Celastrol reduces lung inflammation induced by multiwalled carbon nanotubes in mice via NF-κb-signaling pathway.

Multiwalled carbon nanotubes (MWCNTs) have numerous applications in the field of carbon nanomaterials. However, the associated toxicity concerns have increased significantly because of their widespread use. The inhalation of MWCNTs can lead to nanoparticle deposition in the lung tissue, causing inflammation and health risks. In this study, celastrol, a natural plant medicine with potent anti-inflammatory properties, effectively reduced the number of inflammatory cells, including white blood cells, neutrophils, and lymphocytes, and levels of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in mice lungs exposed to MWCNTs. Moreover, celastrol inhibited the activation of the NF-κB-signaling pathway. This study confirmed these findings by demonstrating comparable reductions in inflammation upon exposure to MWCNTs in mice with the deletion of NF-κB (P50-/-). These results indicate the utility of celastrol as a promising pharmacological agent for preventing MWCNT-induced lung tissue inflammation.

Subchronic toxicity study of ferric oxide nanoparticles through intragastric administration: A 94-d, repeated dose study in Sprague Dawley rats.

In this study, the toxicity of ferric oxide nanoparticles (Fe2O3 NPs) administered through gavage to Sprague Dawley (SD) rats for 94 d, consecutively and the recovery after Fe2O3 NPs withdrawal for 30 d were evaluated. The vehicle control group, low-, medium-, and high-dose groups were administered with the vehicle (0.5% sodium carboxymethyl cellulose [CMC-Na]), 125, 250, and 500 mg/kg of Fe2O3 NPs, respectively, administered every morning for 94 d. There was no significant difference in the body weight, food intake, hematological, blood biochemical, and urine indices of SD rats in each administration group and the control group (P > 0.05). There was no significant difference in organ weight, organ indices, and the coefficient of the visceral brain between the SD rats in the different dosage groups and the SD rats in the vehicle control group (P > 0.05). Histopathological observations showed that there was no correlation between the pathological lesions of the organs observed in this study and the dose of Fe2O3 NPs (P > 0.05). The no-observed-adverse-effect level (NOAEL) dose of Fe2O3 NPs was initially determined to be 500 mg/kg administered to SD rats through oral gavage for 94 d, consecutively, followed by recovery after Fe2O3 NPs withdrawal for 30 d.

Celastrol alleviates oxidative stress induced by multi-walled carbon nanotubes through the Keap1/Nrf2/HO-1 signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) mainly induce oxidative stress through the overproduction of reactive oxygen species (ROS), which can lead to cytotoxicity. Celastrol, a plant-derived compound, can exert antioxidant effects by reducing ROS production. Our results indicated that exposure to MWCNTs decreased cell viability and increased ROS production. Nrf2 knockdown (kd) led to increased ROS production and enhanced MWCNT-induced cytotoxicity. Keap1-kd led to decreased ROS production and attenuated cytotoxicity. Treatment with celastrol significantly decreased ROS production and promoted Keap1 protein degradation through the lysosomal pathway, thereby enhancing the translocation of Nrf2 from the cytoplasm to the nucleus and increasing HO-1 expression. The in vivo results showed that celastrol could alleviate the inflammatory damage of lung tissues, increase the levels of the antioxidants, GSH and SOD, as well as promote the expression of the antioxidant protein, HO-1 in MWCNT-treated mice. Celastrol can alleviate MWCNT-induced oxidative stress through the Keap1/Nrf2/HO-1 signaling pathway.

Evaluation of subchronic toxicity of the compound of diphenhydramine hydrochloride and caffeine after 28 days of repeated oral administration in Sprague-Dawley rats and beagle dogs.

This study was designed to evaluate the subchronic toxicity of the compound of diphenhydramine hydrochloride (DH) and caffeine in Sprague-Dawley (SD) rats and beagle dogs. A total of 180 SD rats (15/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (51, 102, 204 mg/kg), DH group (60 mg/kg), caffeine group (144 mg/kg) and the vehicle control group. Sixty beagle dogs (5/sex/group) were randomly divided into the compound low-, medium- and high-dose groups (male: 14.20, 28.30, 56.60 mg/kg, female: 5.66, 14.20, 28.30 mg/kg), DH group (male: 16.60 mg/kg, female: 8.30 mg/kg), caffeine group (male: 40.00 mg/kg, female: 20.00 mg/kg) and the vehicle control group. Rats and dogs were given continuous oral administration for 28 days following a 28-day recovery period. The adverse effects of the compound on rats and beagle dogs mainly included anorexia and liver function impairment. Most adverse effects induced by administration were reversible. Under the experimental conditions, the no-observed-adverse-effect level (NOAEL) of the compound of DH and caffeine was 51 mg/kg/day for SD rats and 28.30 mg/kg/day (male) and 5.66 mg/kg/day (female) for beagle dogs.

NLRP3 ablation enhances tolerance in heat stroke pathology by inhibiting IL-1ß-mediated neuroinflammation.

BACKGROUND: Patients with prior illness are more vulnerable to heat stroke-induced injury, but the underlying mechanism is unknown. Recent studies suggested that NLRP3 inflammasome played an important role in the pathophysiology of heat stroke. METHODS: In this study, we used a classic animal heat stroke model. Prior infection was mimicked by using lipopolysaccharide (LPS) or lipoteichoic acid (LTA) injection before heat stroke (LPS/LTA 1 mg/kg). Mice survival analysis curve and core temperature (TC) elevation curve were produced. NLRP3 inflammasome activation was measured by using real-time PCR and Western blot. Mice hypothalamus was dissected and neuroinflammation level was measured. To further demonstrate the role of NLRP3 inflammasome, Nlrp3 knockout mice were used. In addition, IL-1ß neutralizing antibody was injected to test potential therapeutic effect on heat stroke. RESULTS: Prior infection simulated by LPS/LTA injection resulted in latent inflammation status presented by high levels of cytokines in peripheral serum. However, LPS/LTA failed to cause any change in animal survival rate or body temperature. In the absence of LPS/LTA, heat treatment induced heat stroke and animal death without significant systemic or neuroinflammation. Despite a decreased level of IL-1ß in hypothalamus, Nlrp3 knockout mice demonstrated no survival advantage under mere heat exposure. In animals with prior infection, their heat tolerance was severely impaired and NLRP3 inflammasome induced neuroinflammation was detected. The use of Nlrp3 knockout mice enhanced heat tolerance and alleviated heat stroke-induced death by reducing mice hypothalamus IL-1ß production with prior infection condition. Furthermore, IL-1ß neutralizing antibody injection significantly extended endotoxemic mice survival under heat stroke. CONCLUSIONS: Based on the above results, NLRP3/IL-1ß induced neuroinflammation might be an important mechanistic factor in heat stroke pathology, especially with prior infection. IL-1ß may serve as a biomarker for heat stroke severity and potential therapeutic method.

Endothelium-Specific GTP Cyclohydrolase I Overexpression Restores Endothelial Function in Aged Mice.

This study tested the hypothesis that endothelium-specific GTP cyclohydrolase I (GTPCH I) overexpression (Tg-GCH) restores age-associated endothelial dysfunction in vivo. Aortic GTPCH I expression and serum nitric oxide (NO) release were measured in young and aged mice. Aortic rings from young and aged wild-type (WT) mice and aged Tg-GCH mice were suspended for isometric tension recording. A hind limb ischemia model was used to measure blood flow recovery. Aged mice showed reduced GTPCH I expression in the aorta and decreased NO levels in serum. Compared with aged WT mice, Tg-GCH significantly elevated NO levels in serum in aged Tg-GCH mice, restored the impaired aortic relaxation in response to acetylcholine, and significantly elevated aortic constriction in response to L-NAME. Importantly, aged Tg-GCH mice displayed a significant increase in blood flow recovery compared with aged WT mice. GTPCH I reduction contributes to aging-associated endothelial dysfunction, which can be retarded by Tg-GCH.

Sorting full angular momentum states with Pancharatnam-Berry metasurfaces based on spiral transformation.

Full angular momentum states constitute a complete and higher state space of a photon, which are significant not only for fundamental study of light but also for practical applications utilizing cylindrical optics such as optical fibers. Here we propose and demonstrate a simple yet effective scheme of combining the spiral transformation with Pancharatnam-Berry (PB) metasurfaces for high-resolution sorting of full angular momentum states. The scheme is verified by successfully sorting full angular momentum states with 7 orbital angular momentum states and 2 spin angular momentum states via numerical simulations and experiments. We expect that our work paves the way for simple high-resolution sorting of full angular momentum states, which could be highly useful in both classical and quantum information systems.

Combined frequency-locking technology of a digital integrated resonator optic gyroscope with a phase-modulated feedback loop.

In the resonator fiber optic gyroscope (RFOG), the conventional laser feedback loop is realized by adjusting the laser central frequency to tracking the resonance point of the resonator. This method generally relies on the laser tuning coefficient and digital-to-analog converter, which inevitably produces quantization error and limits frequency-locking accuracy and gyro resolution. In addition, the output drift caused by low-frequency noise also is a problem with long-term lock-in tests. In this paper, a novel and simple combined frequency-locking technology based on a phase-modulated feedback loop and a laser feedback loop is proposed by using the high-precision tuning of a phase modulator to improve the resolution and suppress the low-frequency drift. Furthermore, it has been proved by experiments that the resolution is increased by 10 times, while the frequency-locking accuracy is improved from 10°/s to 0.5°/s by using the combined frequency-locking mode. In addition, the low-frequency drift is eliminated with the long-term lock-in of RFOG, and the system resolution from 1°/s to 0.1°/s is accurately displayed.

The application of the improved 3D rat testicular cells co-culture model on the in vitro toxicity research of HZ1006.

The aims of the present research are to further validate the application of the improved three-dimensional (3 D) rat testicular cell co-culture model to evaluate the effects of various reprotoxic chemicals on the function of the main somatic cells, as well as on spermatogonial cell differentiation and even spermatogenesis, and to investigate the specific toxicant mechanisms in testes treated with HZ1006, a hydroxamate-based a hydroxamate-based histone deacetylase inhibitor (HDACI). Based on the characteristics of HZ1006, the appropriate exposure duration (8, 16, or 24 days), dosage (0, 3.125, 6.25, 12.5, or 25 µM) and toxic endpoints suitable for detection were selected in the experiments. The results showed inhibition of cell proliferation, reduced testosterone levels, and decreased spermatogonial cell meiosis-specific gene expression, as well as decreased protein levels of androgen receptor (AR) and decreased expression of the AR target gene PSA, accompanied by inhibition of Hdac6 expression after HZ1006 exposure in the 3 D rat testicular cell co-culture model. These findings indicate that the improved 3 D rat testicular cell co-culture model we have established has the potential to become a new testicular toxicity test system that can be used to test toxic characteristics and mechanisms of new compounds and has good application prospects, although more research on the model is required.

Scalable mode division multiplexed transmission over a 10-km ring-core fiber using high-order orbital angular momentum modes.

We propose and demonstrate a scalable mode division multiplexing scheme based on orbital angular momentum modes in ring core fibers. In this scheme, the high-order mode groups of a ring core fiber are sufficiently de-coupled by the large differential effective refractive index so that multiple-input multiple-output (MIMO) equalization is only used for crosstalk equalization within each mode group. We design and fabricate a graded-index ring core fiber that supports 5 mode groups with low inter-mode-group coupling, small intra-mode-group differential group delay, and small group velocity dispersion slope over the C-band for the high-order mode groups. We implement a two-dimensional wavelength- and mode-division multiplexed transmission experiment involving 10 wavelengths and 2 mode groups each with 4 OAM modes, transmitting 32 GBaud Nyquist QPSK signals over all 80 channels. An aggregate capacity of 5.12 Tb/s and an overall spectral efficiency of 9 bit/s/Hz over 10 km are realized, only using modular 4x4 MIMO processing with 15 taps to recover signals from the intra-mode-group mode coupling. Given the fixed number of modes in each mode group and the low inter-mode-group coupling in ring core fibres, our scheme strikes a balance in the trade-off between system capacity and digital signal processing complexity, and therefore has good potential for capacity upscaling at an expense of only modularly increasing the number of mode-groups with fixed-size (4x4) MIMO blocks.

Orbital-angular-momentum mode-group multiplexed transmission over a graded-index ring-core fiber based on receive diversity and maximal ratio combining.

An orbital-angular-momentum (OAM) mode-group multiplexing (MGM) scheme using high-order mode groups (MGs) in a graded-index ring-core fiber (GIRCF) is proposed, in which a receive-diversity architecture is designed for each MG to suppress the mode partition noise resulting from random intra-group mode crosstalk. The signal-to-noise ratio (SNR) of the received signals is further improved by a simple maximal ratio combining (MRC) technique on the receiver side to efficiently take advantage of the diversity gain of the receiver. Intensity-modulated direct-detection (IM-DD) systems transmitting three OAM mode groups with total 100-Gb/s discrete multi-tone (DMT) signals over a 1-km GIRCF and two OAM mode groups with total 40-Gb/s DMT signals over an 18.4-km GIRCF are experimentally demonstrated, respectively, to confirm the feasibility of our proposed OAM-MGM scheme.

On-chip switchable radially and azimuthally polarized vortex beam generation.

Cylindrical vector vortex (CVV) beams, complex light fields that exhibit a vector nature and carry quantized orbital angular momentum (OAM) states, have been widely investigated due to their rich applications. Current technologies to generate CVV beams using individual polarization and spatial phase manipulations suffer from bulky size and low configurability. In this Letter, we propose and experimentally demonstrate an approach to generate CVV beams with a single integrated device based on a silicon nitride microring resonator and embedded top-gratings. The device allows the manipulation of both the polarization and OAM degrees of freedom of light, and enables the generation of both radially and azimuthally polarized CVV beams. In addition, we develop a method to fabricate the devices of shallow-etched top-gratings with only one-step etching. To the best of our knowledge, this novel method provides new capabilities to develop on-chip integrated devices with great ease and flexibility.

Spiral Transformation for High-Resolution and Efficient Sorting of Optical Vortex Modes.

Mode sorting is an essential function for optical multiplexing systems that exploit the orthogonality of the orbital angular momentum mode space. The familiar log-polar optical transformation provides a simple yet efficient approach whose resolution is, however, restricted by a considerable overlap between adjacent modes resulting from the limited excursion of the phase along a complete circle around the optical vortex axis. We propose and experimentally verify a new optical transformation that maps spirals (instead of concentric circles) to parallel lines. As the phase excursion along a spiral in the wave front of an optical vortex is theoretically unlimited, this new optical transformation can separate orbital angular momentum modes with superior resolution while maintaining unity efficiency.

Integrated optical vortex beam receivers.

A simple and ultra-compact integrated optical vortex beam receiver device is presented. The device is based on the coupling between the optical vortex modes and whispering gallery modes in a micro-ring resonator via embedded angular gratings, which provides the selective reception of optical vortex modes with definitive total angular momentum (summation of spin and orbital angular momentum) through the phase matching condition in the coupling process. Experimental characterization confirms the correct detection of the total angular momentum carried by the vortex beams incident on the device. In addition, photonic spin-controlled unidirectional excitation of whispering-gallery modes in the ring receiver is also observed, and utilized to differentiate between left- and right-circular polarizations and therefore unambiguously identify the orbital angular momentum of incident light. Such characteristics provide an effective mode-selective receiver for the eigen-modes in orbital angular momentum fiber transmission where the circularly polarized OAM modes can be used as data communications channels in multiplexed communications or as photonic states in quantum information applications.

Orbital angular momentum mode-demultiplexing scheme with partial angular receiving aperture.

For long distance orbital angular momentum (OAM) based transmission, the conventional whole beam receiving scheme encounters the difficulty of large aperture due to the divergence of OAM beams. We propose a novel partial receiving scheme, using a restricted angular aperture to receive and demultiplex multi-OAM-mode beams. The scheme is theoretically analyzed to show that a regularly spaced OAM mode set remain orthogonal and therefore can be de-multiplexed. Experiments have been carried out to verify the feasibility. This partial receiving scheme can serve as an effective method with both space and cost savings for the OAM communications. It is applicable to both free space OAM optical communications and radio frequency (RF) OAM communications.

Spin and orbital angular momentum and their conversion in cylindrical vector vortices.

The generation of light beams carrying orbital angular momentum (OAM) has been greatly advanced with the emergence of the recently reported integrated optical vortex emitters. Generally, optical vortices emitted by these devices possess cylindrically symmetric states of polarization and spiral phase fronts, and they can be defined as cylindrical vector vortices (CVVs). Using the radiation of angularly arranged dipoles to model the CVVs, these beams as hybrid modes of two circularly polarized scalar vortices are theoretically demonstrated to own well-defined total angular momentum. Moreover, the effect of spin-orbit interactions of angular momentum is identified in the CVVs when the size of the emitting structure varies. This effect results in the diminishing spin component of angular momentum and purer OAM states at large structure radii.

Study on the Friction and Wear Properties of Multiple Rare-Earth-Oxide-Reinforced Resin-Based Friction Materials.

Aiming to solve the problem of thermal decay of resin-based friction materials at high temperatures, rare-earth-lanthanum-oxide-/cerium-oxide-reinforced resin-based friction plates were prepared using a hot-pressing molding process. The effect of lanthanum/cerium oxide with different contents on the mechanical and tribological properties of the resin-based friction of materials was studied, and its mechanism was explored. The result shows that lanthanum/cerium oxide improves the mechanical and tribological properties of materials so that the coefficient of friction of the specimen is more stable on adding lanthanum/cerium oxide at 5% and 1%. Lanthanum/cerium oxide improves antidegradation properties of resin-based material and reduces the high-temperature wear rate by enhancing the interfacial effect so that the wear form of the specimen changes from predominantly adhesive wear to predominantly abrasive wear.

An NIR-II-photoresponsive CoSnO3 nanozyme for mild photothermally augmented nanocatalytic cancer therapy.

The main challenges of nanozyme-based tumor catalytic therapy (NCT) lie in the unsatisfactory catalytic activity accompanied by a complex tumor microenvironment (TME). A few nanozymes have been designed to possess both enzyme-like catalytic activities and photothermal properties; however, the previously reported nanozymes mainly utilize the inefficient and unsafe NIR-I laser, which has a low maximum permissible exposure limit and a limited penetration depth. Herein, we report for the first time an all-in-one strategy to realize mild NIR-II photothermally amplified NCT by synthesizing amorphous CoSnO3 nanocubes with efficient triple enzyme-like catalytic activities and photothermal conversion properties. The presence of Co2+ and Sn4+ endows CoSnO3 nanocubes with the triple enzyme-like catalytic activities, not only achieving enhanced reactive oxygen species (ROS) generation through the Co2+-mediated peroxidase-like catalytic reaction to generate ˙OH and Sn4+-mediated depletion of overexpressed GSH, but also realizing the catalytic decomposition of endogenous H2O2 for relieving tumor hypoxia. More importantly, the obtained CoSnO3 nanocubes with a high photothermal conversion efficiency of 82.1% at 1064 nm could achieve mild hyperthermia (43 °C), which further improves the triple enzyme-like catalytic activities of the CoSnO3 nanozyme. The synergetic therapeutic efficacy of the NIR-II-responsive CoSnO3 nanozyme through mild NIR-II PTT-enhanced NCT could realize all-in-one multimodal tumor therapy to completely eliminate tumors without recurrence. This study will open a new avenue to explore NIR-II-photoresponsive nanozymes for efficient tumor therapy.