Interference of Steroidogenesis by Gold Nanorod Core/Silver Shell Nanostructures: Implications for Reproductive Toxicity of Silver Nanomaterials.

As a widely used nanomaterial in daily life, silver nanomaterials may cause great concern to female reproductive system as they are found to penetrate the blood-placental barrier and gain access to the ovary. However, it is largely unknown about how silver nanomaterials influence ovarian physiology and functions such as hormone production. This study performs in vitro toxicology study of silver nanomaterials, focusing especially on cytotoxicity and steroidogenesis and explores their underlying mechanisms. This study exposes primary rat granulosa cells to gold nanorod core/silver shell nanostructures (Au@Ag NRs), and compares outcomes with cells exposed to gold nanorods. The Au@Ag NRs generate more reactive oxygen species and reduce mitochondrial membrane potential and less production of adenosine triphosphate. Au@Ag NRs promote steroidogenesis, including progesterone and estradiol, in a time- and dose-dependent manner. Chemical reactivity and transformation of Au@Ag NRs are then studied by electron spin resonance spectroscopy and X-ray absorption near edge structure, which analyze the generation of free radical and intracellular silver species. Results suggest that both particle-specific activity and intracellular silver ion release of Au@Ag NR contribute to the toxic response of granulosa cells.

Gold Nanomaterials in Consumer Cosmetics Nanoproducts: Analyses, Characterization, and Dermal Safety Assessment.

Establishment of analytical methods of engineered nanomaterials in consumer products for their human and environmental risk assessment becomes urgent for both academic and industrial needs. Owing to the difficulties and challenges around nanomaterials in complex media, proper chemical separation and biological assays of nanomaterials from nanoproducts needs to be firstly developed. Herein, a facile and rapid method to separate and analyze gold nanomaterials in cosmetics is reported. Gold nanomaterials are successfully separated from different facial or eye creams and their physiochemical properties are analyzed by quantitative and qualitative state-of-the art techniques with high sensitivity or high spatial resolution. In turn, a protocol including quantification of gold by inductively coupled plasma mass spectrometry and thorough characterization of morphology, size distribution, and surface property by electron microscopes, atomic force microscope, and X-ray photoelectron spectroscope is developed. Subsequently, the preliminary toxicity assessment indicates that gold nanomaterials in cosmetic creams have no observable toxicity to human keratinocytes even after 24 h exposure up to a concentration of 200 µg mL-1 . The environmental scanning electron microscope reveals that gold nanomaterials are mostly attached on the cell membrane. Thus, the present study provides a full analysis protocol for toxicity assessment of gold nanomaterials in consumer products (cosmetic creams).

Social exclusion: differences in neural mechanisms underlying direct versus vicarious experience.

Social exclusion stands as a source of social discord and holds substantial research value. Prior investigations on social exclusion have overlooked the interactive relationship between the excluded individuals and the observers. Hence, this study comparatively explores the neural mechanisms underlying the psychological responses of two distinct roles within the same social exclusion context. A total of 35 pairs (19 pairs of females) participated in the experiment. Within each pair, one individual assumed the role of a socially excluded participant (target), while the other acted as a social exclusion observer. Targets engaged in an online ball-passing game where controlled ball allocations to the participants created an exclusion scenario. Meanwhile, observers spectated the targets playing the game. Throughout the ball-passing activity, functional near-infrared spectroscopy (fNIRS) recorded the blood oxygen data in the prefrontal cortex (PFC) and temporoparietal junction (TPJ) of both participants. Our findings revealed varied levels of rejection sensitivity elicited by direct or observed social exclusion experiences. Additionally, distinct patterns of neural activation were observed: targets displayed conditional differences in the medial prefrontal cortex (mPFC), while male observers exhibited conditional activation differences in the mPFC, and female observers showed conditional activation differences in the right dorsolateral prefrontal cortex (dlPFC). This study juxtaposes the behavioral and neural activation variances between targets and observers within the same social context, offering a novel perspective on investigating the neural mechanisms of social exclusion.

In situ label-free X-ray imaging for visualizing the localization of nanomedicines and subcellular architecture in intact single cells.

Understanding the intracellular behaviors of nanomedicines and morphology variation of subcellular architecture impacted by nanomaterial-biology (nano-bio) interactions could help guide the safe-by-design, manufacturing and evaluation of nanomedicines for clinical translation. The in situ and label-free analysis of nano-bio interactions in intact single cells at nanoscale remains challenging. We developed an approach based on X-ray microscopy to directly visualize the 2D or 3D intracellular distribution without labeling at nanometer resolution and analyze the chemical transformation of nanomedicines in situ. Here, we describe an optimized workflow for cell sample preparation, beamline selection, data acquisition and analysis. With several model bionanomaterials as examples, we analyze the localization of nanomedicines in various primary blood cells, macrophages, dendritic cells, monocytes and cancer cells, as well as the morphology of some organelles with soft and hard X-rays. Our protocol has been successfully implemented at three beamline facilities: 4W1A of Beijing Synchrotron Radiation Facility, BL08U1A of Shanghai Synchrotron Radiation Facility and BL07W of the National Synchrotron Radiation Laboratory. This protocol can be completed in ~2-5 d, depending on the cell types, their incubation times with nanomaterials and the selected X-ray beamline. The protocol enables the in situ analysis of the varieties of metal-containing nanomaterials, visualization of intracellular endocytosis, distribution and excretion and corresponding subcellular morphological variation influenced by nanomedicines in cell lines or primary cells by using this universal and robust platform. The results facilitate the understanding of the true principle and mechanism underlying the nano-bio interaction.

Clinical value of γ-glutamyl transpeptidase to platelet ratio and triglyceride measurement in the diagnosis of nonalcoholic fatty liver disease: A cross-sectional study.

Objective: In clinical practice, there are few effective biomarkers for identifying non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate the diagnostic value of γ-glutamyl transpeptidase to platelet ratio (GPR) combined with triglyceride (TG) in NAFLD. Methods: A total of 14,415 individuals participated in the annual physical examination. Multivariate logistic regression analysis was conducted to investigate the exposure factors associated with NAFLD. Spearman's analysis was performed to assess the correlation among the exposure factors of NAFLD. Furthermore, the diagnostic efficacy of the combination of GPR and TG in NAFLD was analyzed using the receiver operating characteristic curve (ROC). Results: The results of the multivariate logistic regression analysis showed that BMI (OR = 1.619), Systolic Blood Pressure (SBP) (OR = 1.014), Diastolic Blood Pressure (DBP) (OR = 1.028), GPR (OR = 12.809), and TG (OR = 2.936) were all risk factors for NAFLD, while HDL-C (OR = 0.215) was a protective factor. Spearman correlation analysis revealed significant positive correlations between GPR and SBP, DBP, BMI, TG (p < 0.01), but a negative correlation between GPR and HDL-C (p < 0.01). TG was only positively correlated with GPR (p < 0.001). ROC curve analysis demonstrated that the area under the curve (AUC) of GPR combined with TG for diagnosis of NAFLD was 0.855 (95 % CI: 0.819-0.891), sensitivity was 83.45 % and specificity was 73.56 %. Conclusion: This study indicated that high levels of GPR and TG were risk factors for NAFLD and demonstrated good clinical value in diagnosing NAFLD.

Analysis of nanomaterial biocoronas in biological and environmental surroundings.

A biomolecular coating, or biocorona, forms on the surface of engineered nanomaterials (ENMs) immediately as they enter biological or environmental systems, defining their biological and environmental identity and influencing their fate and performance. This biomolecular layer includes proteins (the protein corona) and other biomolecules, such as nucleic acids and metabolites. To ensure a meaningful and reproducible analysis of the ENMs-associated biocorona, it is essential to streamline procedures for its preparation, separation, identification and characterization, so that studies in different labs can be easily compared, and the information collected can be used to predict the composition, dynamics and properties of biocoronas acquired by other ENMs. Most studies focus on the protein corona as proteins are easier to monitor and characterize than other biomolecules and play crucial roles in receptor engagement and signaling; however, metabolites play equally critical roles in signaling. Here we describe how to reproducibly prepare and characterize biomolecule-coated ENMs, noting especially the steps that need optimization for different types of ENMs. The structure and composition of the biocoronas are characterized using general methods (transmission electron microscopy, dynamic light scattering, capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry) as well as advanced techniques, such as transmission electron cryomicroscopy, synchrotron-based X-ray absorption near edge structure and circular dichroism. We also discuss how to use molecular dynamic simulation to study and predict the interaction between ENMs and biomolecules and the resulting biocorona composition. The application of this protocol can provide mechanistic insights into the formation, composition and evolution of the ENM biocorona, ultimately facilitating the biomedical and agricultural application of ENMs and a better understanding of their impact in the environment.

High-efficiency encapsulation of Pt nanoparticles into the channel of carbon nanotubes as an enhanced electrocatalyst for methanol oxidation.

Pt-based nanostructures serving as anode catalysts for the methanol oxidation reaction (MOR) have been widely studied for many years. Nevertheless, challenging issues such as poor reaction kinetics and the short-term stability of the MOR are the main drawbacks of such catalysts and limit their applications. Herein, we have developed a facile approach to encapsulate Pt nanoparticles (NPs) inside the nanochannels of porous carbon nanotubes (CNTs; Pt-in-CNTs) as a new enhanced electrocatalytic material. The as-prepared CNTs offer simultaneously ordered diffusion channels for ions and a confinement effect for the NPs, which both facilitate the promotion of catalytic kinetics and avoid the Ostwald ripening of Pt NPs, thus leading to high activity and durable cycle life as an anode catalyst for MOR. This work provides a new approach for enhancing the stability and activity by optimizing the structure of the catalyst, and the Pt-in-CNTs represent the most durable catalysts ever reported for MOR.

Bioavailability of nanomaterials: bridging the gap between nanostructures and their bioactivity.

Instead of the nanostructure and biological activity, this perspective highlights the metabolic processes from biotransformation to bioavailability, to bridge the gap between the cradle (structure design) and endpoint (efficacy and/or safety) of nanomedicines.

Advanced Light Source Analytical Techniques for Exploring the Biological Behavior and Fate of Nanomedicines.

Exploration of the biological behavior and fate of nanoparticles, as affected by the nanomaterial-biology (nano-bio) interaction, has become progressively critical for guiding the rational design and optimization of nanomedicines to minimize adverse effects, support clinical translation, and aid in evaluation by regulatory agencies. Because of the complexity of the biological environment and the dynamic variations in the bioactivity of nanomedicines, in-situ, label-free analysis of the transport and transformation of nanomedicines has remained a challenge. Recent improvements in optics, detectors, and light sources have allowed the expansion of advanced light source (ALS) analytical technologies to dig into the underexplored behavior and fate of nanomedicines in vivo. It is increasingly important to further develop ALS-based analytical technologies with higher spatial and temporal resolution, multimodal data fusion, and intelligent prediction abilities to fully unlock the potential of nanomedicines. In this Outlook, we focus on several selected ALS analytical technologies, including imaging and spectroscopy, and provide an overview of the emerging opportunities for their applications in the exploration of the biological behavior and fate of nanomedicines. We also discuss the challenges and limitations faced by current approaches and tools and the expectations for the future development of advanced light sources and technologies. Improved ALS imaging and spectroscopy techniques will accelerate a profound understanding of the biological behavior of new nanomedicines. Such advancements are expected to inspire new insights into nanomedicine research and promote the development of ALS capabilities and methods more suitable for nanomedicine evaluation with the goal of clinical translation.

In vivo percutaneous permeation of gold nanomaterials in consumer cosmetics: implication in dermal safety assessment of consumer nanoproducts.

The increasing emergence of nano-cosmetics in the marketplace provokes safety concerns with respect to percutaneous permeation and toxicity of nanomaterials inside the human body. In this study, in vivo percutaneous permeation and dermal safety of cosmetic cream containing Au nanosheets and extracted Au nanosheets from cosmetic creams are investigated with guinea pigs. Quantitative percutaneous permeation data suggests that Au nanosheets in cosmetic creams permeate into the skin epidermis, dermis, and subcutaneous layer after 10 d cutaneous exposure, but cannot enter the systemic circulation. However, more Au nanosheets are accumulated in the skin and the permeation of Au nanosheets increased after embedded into the cream matrix. Synchrotron radiation X-ray fluorescence (SRXRF) imaging reveals that Au nanosheets in cosmetics penetrate mainly through hair follicles in a time-dependent manner. Cosmetic creams rather than extracted Au nanosheets decrease the cell viability of keratinocytes and slightly induce apoptosis/necrosis of keratinocytes and skin dermal fibroblasts. Intriguingly, the growth of hair is inhibited by the cosmetic cream and the extracted Au nanosheets revealed by HE staining and immunohistochemistry (IHC) assay. Altogether this study provides insights into the comprehensive understanding of percutaneous permeation and dermal safety of cosmetic creams containing Au nanosheets. This work provides reliable methods to study the skin permeation, biodistribution, and dermal safety of nano-cosmetics and reminds the community of the crucial need to combine the assays at molecular, cellular, and organ levels in nanotoxicology research.

Molybdenum derived from nanomaterials incorporates into molybdenum enzymes and affects their activities in vivo.

Many nanoscale biomaterials fail to reach the clinical trial stage due to a poor understanding of the fundamental principles of their in vivo behaviour. Here we describe the transport, transformation and bioavailability of MoS2 nanomaterials through a combination of in vivo experiments and molecular dynamics simulations. We show that after intravenous injection molybdenum is significantly enriched in liver sinusoid and splenic red pulp. This biodistribution is mediated by protein coronas that spontaneously form in the blood, principally with apolipoprotein E. The biotransformation of MoS2 leads to incorporation of molybdenum into molybdenum enzymes, which increases their specific activities in the liver, affecting its metabolism. Our findings reveal that nanomaterials undergo a protein corona-bridged transport-transformation-bioavailability chain in vivo, and suggest that nanomaterials consisting of essential trace elements may be converted into active biological molecules that organisms can exploit. Our results also indicate that the long-term biotransformation of nanomaterials may have an impact on liver metabolism.

Immunological Responses Induced by Blood Protein Coronas on Two-Dimensional MoS2 Nanosheets.

Two-dimensional (2D) nanosheets (NSs) have a large surface area, high surface free energy, and ultrathin structure, which enable them to more easily penetrate biological membranes and promote adsorption of drugs and proteins. NSs are capable of adsorbing a large amount of blood proteins to form NSs-protein corona complexes; however, their inflammatory effects are still unknown. Therefore, we investigated the pro-inflammatory effect of 2D model nanosheet structures, molybdenum disulfide (MoS2), and the MoS2 NSs-protein complexes with four abundant proteins in human blood, i.e., human serum albumin (HSA), transferrin (Tf), fibrinogen (Fg), and immunoglobulin G (IgG). The interactions between the NSs and the proteins were analyzed by quantifying protein adsorption, determining binding affinity, and correlating structural changes in the protein corona with the uptake of NSs by macrophages and the subsequent inflammatory response. Although all of the NSs-protein complexes induced inflammation, IgG-coated and Fg-coated NSs triggered much stronger inflammatory effects by producing and releasing more cytokines. Among the four proteins, IgG possessed the highest proportion of ß-sheets and led to fewer secondary structure changes on the MoS2 nanosheets. This can facilitate uptake and produce a stronger pro-inflammatory response in macrophages due to the recognition of an NSs-IgG complex by Fc gamma receptors and the subsequent activation of the NF-κB pathways. Our results demonstrate that the blood protein components contribute to the inflammatory effects of nanosheets and provide important insights for the nanosafety evaluation and the rational design of nanomedicines in the future.

New power of self-assembling carbonic anhydrase inhibitor: Short peptide-constructed nanofibers inspire hypoxic cancer therapy.

Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX-targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX-related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.

Gd-Hybridized Plasmonic Au-Nanocomposites Enhanced Tumor-Interior Drug Permeability in Multimodal Imaging-Guided Therapy.

An original gadolinium-hybridized plasmonic gold nanocomposite is fabricated to provide an insightful and attractive strategy to overcome both the physiological and pathological barriers of tumor, and increase the transportation and permeability of imaging agents and drugs in tumor interior for achieving high-sensitive multimodal imaging and simultaneously improving the therapeutic efficacy of cancer.

Rapid Degradation and High Renal Clearance of Cu3BiS3 Nanodots for Efficient Cancer Diagnosis and Photothermal Therapy in Vivo.

A key challenge for the use of inorganic nanomedicines in clinical applications is their long-term accumulation in internal organs, which raises the common concern of the risk of adverse effects and inflammatory responses. It is thus necessary to rationally design inorganic nanomaterials with proper accumulation and clearance mechanism in vivo. Herein, we prepared ultrasmall Cu3BiS3 nanodots (NDs) as a single-phased ternary bimetal sulfide for photothermal cancer therapy guided by multispectral optoacoustic tomography (MSOT) and X-ray computed tomography (CT) due to bismuth's excellent X-ray attenuation coefficient. We then monitored and investigated their absorption, distribution, metabolism, and excretion. We also used CT imaging to demonstrate that Cu3BiS3 NDs can be quickly removed through renal clearance, which may be related to their small size, rapid chemical transformation, and degradation in an acidic lysosomal environment as characterized by synchrotron radiation-based X-ray absorption near-edge structure spectroscopy. These results reveal that Cu3BiS3 NDs act as a simple but powerful "theranostic" nanoplatform for MSOT/CT imaging-guided tumor ablation with excellent metabolism and rapid clearance that will improve safety for clinical applications in the future.

Gadolinium(III)-Chelated Silica Nanospheres Integrating Chemotherapy and Photothermal Therapy for Cancer Treatment and Magnetic Resonance Imaging.

The combination of therapy and diagnosis has been emerging as a promising strategy for cancer treatment. To realize chemotherapy, photothermal therapy, and magnetic resonance imaging (MRI) in one system, we have synthesized a new magnetic nanoparticle (Gd@SiO2-DOX/ICG-PDC) integrating doxorubicin (DOX), indocyanine green (ICG), and gadolinium(III)-chelated silica nanospheres (Gd@SiO2) with a poly(diallyldimethylammonium chloride) (PDC) coating. PDC coating serves as a polymer layer to protect from quick release of drugs from the nanocarriers and increase cellular uptake. The DOX release from Gd@SiO2-DOX/ICG-PDC depends on pH and temperature. The process will be accelerated in the acidic condition than in a neutral pH 7.4. Meanwhile, upon laser irradiation, the photothermal effects promote DOX release and improve the therapeutic efficacy compared to either DOX-loaded Gd@SiO2 or ICG-loaded Gd@SiO2. Moreover, MRI results show that the Gd@SiO2-PDC nanoparticles are safe T1-type MRI contrast agents for imaging. The Gd@SiO2-PDC nanoparticles loaded with DOX and ICG can thus act as a promising theranostic platform for multimodal cancer treatment.