A Self-Amplifying ROS-Responsive Nanoplatform for Simultaneous Cuproptosis and Cancer Immunotherapy.

Cuproptosis is an emerging cell death pathway that depends on the intracellular Cu ions. Elesclomol (ES) as an efficient Cu ionophore can specifically transport Cu into mitochondria and trigger cuproptosis. However, ES can be rapidly removed and metabolized during intravenous administration, leading to a short half-life and limited tumor accumulation, which hampers its clinical application. Here, the study develops a reactive oxygen species (ROS)-responsive polymer (PCP) based on cinnamaldehyde (CA) and polyethylene glycol (PEG) to encapsulate ES-Cu compound (EC), forming ECPCP. ECPCP significantly prolongs the systemic circulation of EC and enhances its tumor accumulation. After cellular internalization, the PCP coating stimulatingly dissociates exposing to the high-level ROS, and releases ES and Cu, thereby triggering cell death via cuproptosis. Meanwhile, Cu2+-stimulated Fenton-like reaction together with CA-stimulated ROS production simultaneously breaks the redox homeostasis, which compensates for the insufficient oxidative stress treated with ES alone, in turn inducing immunogenic cell death of tumor cells, achieving simultaneous cuproptosis and immunotherapy. Furthermore, the excessive ROS accelerates the stimuli-dissociation of ECPCP, forming a positive feedback therapy loop against tumor self-alleviation. Therefore, ECPCP as a nanoplatform for cuproptosis and immunotherapy improves the dual antitumor mechanism of ES and provides a potential optimization for ES clinical application.

Glutamate affects self-assembly, protein corona, and anti-4 T1 tumor effects of melittin/vitamin E-succinic acid-(glutamate)n nanoparticles.

Melittin (M) has attracted increasing attention for its significant antitumor effects and various immunomodulatory effects. However, various obstacles such as the short plasma half-life and adverse reactions restrict its application. This study aimed to systematically investigate the self-assembly mechanism, components of the protein corona, targeting behavior, and anti-4 T1 tumor effect of vitamin E-succinic acid-(glutamate)n /melittin nanoparticles with varying amounts of glutamic acid. Here, we present a new vitamin E-succinic acid-(glutamate)5 (E5), vitamin E-succinic acid-(glutamate)10 (E10) or vitamin E-succinic acid-(glutamate)15 (E15), and their co-assembly system with positively charged melittin in water. The molecular dynamics simulations demonstrated that the electrostatic energy and van der Waals force in the system decreased significantly with the increase in the amount of glutamic acid. The melittin and E15 system exhibited the optimal stability for nanoparticle self-assembly. When nanoparticles derived from different self-assembly systems were co-incubated with plasma from patients with breast cancer, the protein corona showed heterogeneity. In vivo imaging demonstrated that an increase in the number of glutamic acid residues enhanced circulation duration and tumor-targeting effects. Both in vitro and in vivo antitumor evaluation indicated a significant increase in the antitumor effect with the addition of glutamic acid. According to our research findings, the number of glutamic acid residues plays a crucial role in the targeted delivery of melittin for immunomodulation and inhibition of 4 T1 breast cancer. Due to the self-assembly capabilities of vitamin E-succinic acid-(glutamate)n in water, these nanoparticles carry significant potential for delivering cationic peptides such as melittin.

Identification of potential prognostic biomarkers for hepatocellular carcinoma.

Background: The incidence of liver cancer is increasing every year. Hepatocellular carcinoma (HCC) accounts for nearly 90% of liver cancer, and the overall 5-year survival rate of become of Hepatocellular carcinoma patients less than 20%. However, the molecular mechanism of HCC progression and prognosis still requires further exploration. Methods: In this study, we downloaded the gene expression data from the Cancer Genome Atlas (TCGA) Genomic Data and the official website of GEO database. Weighted gene co-expression network analysis (WGCNA) and Pearson's correlation coefficient were utilized to detect the gene modules. The shared differentially-expressed genes (DEGs) were screened out by a Venn diagram, and the hub genes were identified through protein-protein interaction (PPI) network analyses. GO and KEGG enrichment analyses were constructed for these hub genes. Overall survival (OS) and correlation analysis were conducted to investigate the relationship between the hub genes and clinical features. Results: We screened out 27 shared DEGs, and the mainly enriched GO terms were mitotic nuclear division, chromosomal region, and tubulin binding. Furthermore, the top three enriched KEGG pathways were "cell cycle", "oocyte meiosis", and "p53 signaling pathway". According to the Maximal Clique Centrality (MCC) algorithm, the top 10 candidate hub genes were MYC, MCM3, CDC20, CCNB1, BIRC5, UBE2C, TOP2A, RRM2, TK1, and PTTG1, among which BIRC5, CDC20, and UBE2C showed a strong correlation with the OS. Conclusions: Three hub genes (BIRC5, CDC20, and UBE2C) were identified and found to be correlated to the progression and prognosis of HCC. These may become potential targets for HCC therapy.

Quantifying public health benefits of PM2.5 reduction and spatial distribution analysis in China.

In recent years, particulate matter (PM) air pollution has become a significant and growing public health problem in China. In this study, the daily PM2.5 exposure level at a spatial resolution of 100 km2 was simulated based on the data of 1328 monitoring sites and the Voronoi Neighborhood Averaging (VNA) interpolation method. The results reveal that the daily mean PM2.5 concentration reduced from 47.82 µg/m3 (2016) to 40.87 µg/m3 (2018), a reduction of 14.53%. We first calculated the heath impacts and economic benefits of this reduction (Scenario 1) by using Environmental Benefits Mapping and Analysis Program (BenMAP). The estimated avoided premature mortalities for all-cause, cardiovascular diseases, respiratory diseases, and lung cancer were in the range of 7214 to 81,681 cases (total of 154,176 cases). The estimated economic benefits based on willingness to pay (WTP) ranged from 3.96 to 44.85 billion RMB (total of 84.66 billion RMB). Moreover, the PM2.5 concentration in the control scenario was rolled back to the Grade I standards (35 µg/m3, Scenario 2). The avoided deaths are in the range of 58,820 to 590,464 cases (total of 1,217,671 cases). The estimated monetary value of the avoided cases of all health endpoints range from 36.63 to 367.66 billion RMB based on WTP (total of 758.21 billion RMB). In addition, the spatial autocorrelation analysis reveals that the distribution of both avoided premature mortality and economic benefits exhibit a certain spatial aggregation.