Ligand Mediation for Tunable and Oxide Suppressed Surface Gold-Decorated Liquid Metal Nanoparticles.

Gallium-based liquid metal systems hold vast potential in materials science. However, maximizing their possibilities is hindered by gallium's native oxide and interfacial functionalization. In this study, small-molecule ligands are adopted as surfactants to modify the surface of eutectic gallium indium (EGaIn) nanoparticles and suppress oxidation. Different p-aniline derivatives are explored. Next, the reduction of chloroanric acid (HAuCl4 ) onto these p-aniline ligand modified EGaIn nanoparticles is investigated to produce gold-decorated EGaIn nanosystems. It is found that by altering the concentrations of HAuCl4 or the p-aniline ligand, the formation of gold nanoparticles (AuNPs) on EGaIn can be manipulated. The reduction of interfacial oxidation and presence of AuNPs enhances electrical conductivity, plasmonic performance, wettability, stability, and photothermal performance of all the p-aniline derivative modified EGaIn. Of these, EGaIn nanoparticles covered with the ligand of p-aminobenzoic acid offer the most evenly distributed AuNPs decoration and perfect elimination of gallium oxides, resulting in the augmented electrical conductivity, and highest wettability suitable for patterning, enhanced aqueous stability, and favorable photothermal properties. The proof-of-concept application in photothermal therapy of cancer cells demonstrates significantly enhanced photothermal conversion performance along with good biocompatibility. Due to such unique characteristics, the developed gold-decorated EGaIn nanodroplets are expected to offer significant potential in precise medicine.

Development of alveolar-capillary-exchange (ACE) chip and its application for assessment of PM2.5-induced toxicity.

Although standard two-dimensional (2D) cell culture is an effective tool for cell studies, monolayer cultivation can yield imperfect or misleading information about numerous biological functions. In this study, we developed an alveolar-capillary exchange (ACE) chip aiming to simulate the cellular microenvironment at the alveolar-capillary interface. The ACE chip was designed with two chambers for culturing alveolar epithelial cells and vascular endothelial cells separately, which are separated by a microporous polycarbonate film that allows for the exchange of soluble biomolecules. Using this model, we further tested the toxic effects of fine particulate matter (PM2.5), a form of airborne pollutant known to induce adverse effects on human respiratory system. These effects are largely associated with the ability of PM2.5 to penetrate the alveoli, where it negatively affects the pulmonary function. Our results indicate that alveolar epithelial cells cultured in the ACE chip in solo and coculture with vascular endothelial cells underwent oxidative injury-induced apoptosis mediated via the PEAK-eIF2α signaling pathway of endoplasmic reticulum stress. The use of ACE chip in an alveolar epithelial cell-vascular endothelial cell coculture model revealed cellular vulnerability to PM2.5. Therefore, this chip provides a feasible surrogate approach in vitro for investigating and simulating the cellular microenvironment responses associated with ACE in vivo.

BMS-794833 reduces anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway.

Background: Osteosarcoma, a tumor that originates from bone cells, has a poor prognosis and a high degree of malignancy. Anlotinib, a small-molecule multi-target tyrosine kinase inhibitor (TKI), is the first-line drug in treating osteosarcoma, especially in late-stage osteosarcoma. However, patients often develop resistance after using anlotinib for a certain period, which poses a challenge to its further clinical application. Recently, several TKIs, for instance regorafenib and cabozantinib, have showed clinical interest in treating osteosarcoma and target both vascular endothelial growth factor receptor (VEGFR) and mesenchymal epithelial transition factor (c-MET). Therefore, the identification of new TKI warrants further investigation. Methods: We performed CCK8 aasays to confirm that BMS-794833 sensitization osteosarcoma cells to anlotinib. Bioinformatics analysis and rescue experiments showed that the reduce of resistance were dependent on the VEGFR/Ras/CDK2 pathway. Cell line based xenograft model were used to demonstrate that BMS-794833 and anlotinib could synergistically treat OS. Results: Here, we found that BMS-794833 reduced anlotinib resistance in osteosarcoma by targeting the VEGFR/Ras/CDK2 pathway. CCK8 assay showed that BMS-794833 significantly improved the resistance of osteosarcoma cells to anlotinib. The results of rescue experiments showed that the regulatory effects of BMS-794833 on the proliferation and drug resistance of osteosarcoma cells were dependent on the VEGFR/Ras/CDK2 pathway. In addition, BMS-794833 affected the resistance of osteosarcoma cells to anlotinib through epithelial-mesenchymal transition (EMT) and apoptosis pathways. More importantly, BMS-794833 and anlotinib exerted synergistic therapeutic effects against osteosarcoma in vivo. Conclusion: Altogether, this study reveals a new (VEGFR)-targeting drug that can be combined with anlotinib for the treatment of osteosarcoma, which provides an important theoretical basis for overcoming anlotinib resistance.

Metalloproteins as risk factors for osteoarthritis: improving and understanding causal estimates using Mendelian randomization.

Osteoarthritis (OA) is one of the most prevalent musculoskeletal disorders and a primary cause of pain and disability among the elderly population. Research on the relationship between metalloproteins (MPs) and OA is limited, and causality remains unclear. Our objective is to utilize Mendelian randomization (MR) to explore the possible causal relationship between MPs and OA. The data on MPs were derived from a Genome-Wide Association Study (GWAS) analysis involving 3301 samples. The GWAS data for OA were obtained from an analysis involving 462,933 European individuals. In this study, a variety of two-sample Mendelian randomization methods (two-sample MR) to evaluate the causal effect of MPs on OA, including inverse variance weighted method (IVW), MR-Egger method, weighted median method (WM), simple mode, weight mode, and Wald ratio. The primary MR analysis using the IVW method reveals a significant negative correlation between Metallothionein-1F (MT-1F), zinc finger protein 134 (ZNF134), calcium/calmodulin-dependent protein kinase type 1D (CAMK1D), and EF-hand calcium-binding domain-containing protein 14 (EFCAB14) with the occurrence of osteoarthritis (OA) (p value < 0.05). However, no causal relationship was observed in the opposite direction between these MPs and OA. Notably, even in combined models accounting for confounding factors, the negative association between these four MPs and OA remained significant. Sensitivity analysis demonstrated no evidence of horizontal pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the results. In this study, we have established a conspicuous association between four distinct MPs and OA. This discovery augments our understanding of potential avenues for the diagnosis and treatment of this condition. Key Points • The MR method was employed to assess the relationship between MPs and OA. • A total of four types of MPs have demonstrated inhibitory effects on the occurrence of OA.

AP003352.1/miR-141-3p axis enhances the proliferation of osteosarcoma by LPAR3.

Osteosarcoma (OS) is a highly malignant tumor with a poor prognosis and a growing incidence. LncRNAs and microRNAs control the occurrence and development process of osteosarcoma through ceRNA patterns. The LPAR3 gene is important in cancer cell proliferation, apoptosis and disease development. However, the regulatory mechanism of the ceRNA network through which LPAR3 participates in osteosarcoma has not been clarified. Herein, our study demonstrated that the AP003352.1/miR-141-3p axis drives LPAR3 expression to induce the malignant progression of osteosarcoma. First, the expression of LPAR3 is regulated by the changes in AP003352.1 and miR-141-3p. Similar to the ceRNA of miR-141-3p, AP003352.1 regulates the expression of LPAR3 through this mechanism. In addition, the regulation of AP003352.1 in malignant osteosarcoma progression depends to a certain degree on miR-141-3p. Importantly, the AP003352.1/miR-141-3p/LPAR3 axis can better serve as a multi-gene diagnostic marker for osteosarcoma. In conclusion, our research reveals a new ceRNA regulatory network, which provides a novel potential target for the diagnosis and treatment of osteosarcoma.

A Time-Series Analysis on the Association Between Fine Particulate Matter and Daily Mortality - Shijiazhuang City, Hebei Province, China, 2015-2020.

Introduction: Shijiazhuang is one of the most polluted cities in China, but few studies have investigated the acute impact of fine particulate matter (PM2.5) on mortality in this city. We assessed associations between PM2.5 and cause-specific mortality during 2015 to 2020. Methods: We obtained air quality data from Shijiazhuang Ecology and Environment Bureau, meteorological data from Shijiazhuang Meteorological Bureau, and mortality data from Shijiazhuang CDC's Cause of Death Reporting System for our analyses. We used a quasi-Poisson regression generalized additive model to assess excess risk of death for a single time-lag and for moving average time-lags of 0-7 days, stratifying by year, sex, age, and education. Results: There were 76,859 non-accidental deaths recorded in Shijiazhuang during the study period. The daily concentration of PM2.5 ranged from 6.3 µg/m3 to 625.3 µg/m3, and the annual mean concentration was 77.6 µg/m3. Regression analysis showed that an increment of PM2.5 of 10 µg/m3 in a two-day average concentration (lag01) was associated with 0.47% [95% Confidence Interval (CI): 0.24%, 0.70%], 0.49% (95% CI: 0.19%, 0.79%), and 0.72% (95% CI: 0.22%, 1.23%) increases in non-accidental deaths, cardiovascular disease deaths, and respiratory disease deaths, respectively. With reduction of PM2.5 concentration, impact of PM2.5 on respiratory disease deaths decreased, but the impact of PM2.5 on total non-accidental deaths and circulatory disease deaths did not change significantly. Conclusion: Although PM2.5 has been greatly reduced in recent years, PM2.5 pollution is still serious in Shijiazhuang. PM2.5 was significantly associated with non-accidental death, cardiovascular disease death, and respiratory disease death. As PM2.5 concentrations decreased, risk of death from respiratory diseases also decreased.

Genotoxicity of chloroacetamide herbicides and their metabolites in vitro and in vivo.

The toxicity of chloroacetamide herbicide in embryo development remains unclear. Acetochlor (AC) is a chloroacetamide that metabolizes into 2­ethyl­6­methyl-2-chloroacetanilide (CMEPA) and 6­ethyl­o­toluidine (MEA). The present study determined the potential effect of AC and its metabolites on embryo development. Both HepG2 cells and zebrafish embryos were exposed to AC, CMEPA and MEA in the presence or absence of co­treatment with anti­reactive oxygen species (ROS) reagent N­acetylcysteine. The generation of ROS, levels of superoxide dismutase (SOD) and glutathione (GSH) in HepG2 cells and lactate dehydrogenase (LDH) leakage from HepG2 cells were investigated. The effects of AC, CMEPA and MEA on DNA breakage, MAPK/ERK pathway activity, viability and apoptosis of HepG2 cells were examined by comet assay, western blotting, MTT assay and flow cytometry, respectively. Levels of LDH, SOD and GSH in zebrafish embryos exposed to AC, CMEPA and MEA were measured. The hatching and survival rates of zebrafish embryos exposed to AC, CMEPA and MEA, were determined, and apoptosis of hatched fish was investigated using acridine orange staining. The present data showed AC, CMEPA and MEA induced generation of ROS and decreased levels of SOD and GSH in HepG2 cells, which in turn promoted DNA breakage and LDH leakage from cells, ultimately inhibiting cell viability and inducing apoptosis, as well as phosphorylation of JNK and P38. However, co­treatment with N­acetylcysteine alleviated the pro­apoptosis effect of AC and its metabolites. Moreover, exposure to AC, CMEPA and MEA lead to toxicity of zebrafish embryos with decreased SOD and GSH and increased LDH levels and cell apoptosis, ultimately decreasing the hatching and survival rates of zebrafish, all of which was attenuated by treatment with N­acetylcysteine. Therefore, AC and its metabolites (CMEPA and MEA) showed cytotoxicity and embryo development toxicity.