MOF-derived cobalt-iron containing nanocomposite with cascade-catalytic activities for multimodal synergistic tumor therapy.

Reactive oxygen species (ROS)-driven chemodynamic therapy has emerged as a promising anti-tumor strategy. However, the insufficient hydrogen peroxide (H2O2) supply in tumor microenvironment results in a low Fenton reaction rate and subsequently poor ROS production and therapeutic efficacy. Herein, we report on a new nanocomposite MIL-53@ZIF-67/S loaded with doxorubicin and glucose oxidase, which is decomposed under the acidic tumor microenvironment to release Fe3+, Co3+, glucose oxidase, and doxorubicin. The released content leads to synergistic anti-tumor effect through the following manners: 1) doxorubicin is directly used for chemotherapy; 2) Fe3+and Co3+ result in glutathione depletion and Fenton reaction activation through Fe2+ and Co2+ generation to achieve chemodynamic therapy; 3) glucose oxidase continuously catalyzes glucose consumption to induce starvation of the cancer cells, and 4) at the same time the produced gluconic acid and H2O2 significantly promote Fenton reaction and further boost chemodynamic therapy. This work not only demonstrates the high anti-tumor effect of the new nanocomposite, but also provides an innovative strategy for the development of a multi-in-one nanoplatform for cancer therapy.

MiR-92a-2-5p suppresses esophageal squamous cell carcinoma cell proliferation and invasion by targeting PRDX2.

MicroRNAs (miRNAs) can function as negative regulators of gene expression by binding to the 3'-untranslated region (3'-UTR) of target genes. The aberrant expression of miRNAs in neoplasm is extensively associated with tumorigenesis and cancer progression, including esophageal squamous cell carcinoma (ESCC). Our previous investigation has identified the oncogenic roles of Peroxiredoxin2 (PRDX2) in ESCC progression; however, its upstream regulatory mechanism remains to be elucidated. By merging the prediction results from miRWalk2.0 and miRNA differential expression analysis results based on The Cancer Genome Atlas Esophageal Carcinoma (TCGA-ESCA) database, eight miRNA candidates were predicted to be the potential regulatory miRNAs of PRDX2, followed by further identification of miR-92a-2-5p as the putative miRNA of PRDX2. Subsequent functional studies demonstrated that miR-92a-2-5p can suppress ESCC cell proliferation and migration, as well as tumor growth in subcutaneous tumor xenograft models, which might be mediated by the suppression of AKT/mTOR and Wnt3a/ß-catenin signaling pathways upon miR-92a-2-5p mimic transfection condition. These data revealed the tumor suppressive functions of miR-92a-2-5p in ESCC by targeting PRDX2.

Leveraging a disulfidptosis-related signature to predict the prognosis and immunotherapy effectiveness of cutaneous melanoma based on machine learning.

BACKGROUND: Disulfidptosis is a recently discovered programmed cell death pathway. However, the exact molecular mechanism of disulfidptosis in cutaneous melanoma remains unclear. METHODS: In this study, clustering analysis was performed using data from public databases to construct a prognostic model, which was subsequently externally validated. The biological functions of the model genes were then investigated through various experimental techniques, including qRT-PCR, Western blotting, CCK-8 assay, wound healing assay, and Transwell assay. RESULTS: We constructed a signature using cutaneous melanoma (CM) data, which accurately predicts the overall survival (OS) of patients. The predictive value of this signature for prognosis and immune therapy response was validated using multiple external datasets. High-risk CM subgroups may exhibit decreased survival rates, alterations in the tumor microenvironment (TME), and increased tumor mutation burden. We initially verified the expression levels of five optimum disulfidptosis-related genes (ODRGs) in normal tissues and CM. The expression levels of these genes were further confirmed in HaCaT cells and three melanoma cell lines using qPCR and protein blotting analysis. HLA-DQA1 emerged as the gene with the highest regression coefficient in our risk model, highlighting its role in CM. Mechanistically, HLA-DQA1 demonstrated the ability to suppress CM cell growth, proliferation, and migration. CONCLUSION: In this study, a novel signature related to disulfidptosis was constructed, which accurately predicts the survival rate and treatment sensitivity of CM patients. Additionally, HLA-DQA1 is expected to be a feasible therapeutic target for effective clinical treatment of CM.

A hollow Co3-xCuxS4 with glutathione depleting and photothermal properties for synergistic dual-enhanced chemodynamic/photothermal cancer therapy.

Chemodynamic therapy has become an emerging cancer treatment strategy, in which tumor cells are killed through toxic reactive oxygen species (ROS), especially hydroxyl radicals (˙OH) produced by the Fenton reaction. Nevertheless, low ROS generation efficiency and ROS depletion by cellular antioxidant systems are still the main obstacles in chemodynamic therapy. In the present work, we propose a dually enhanced chemodynamic therapy obtained by inhibiting ˙OH consumption and promoting ˙OH production based on the administration of bimetallic sulfide Co3-xCuxS4 nanoparticles functionalized by polyethylene glycol. These bimetallic nanoparticles display glutathione depleting and photothermal properties. The nanoparticles are gradually degraded in a tumor microenvironment, resulting in Co2+ and Cu2+ release. The released Co2+ triggers a Fenton-like reaction that turns endogenous hydrogen peroxide into highly toxic ˙OH. In the cellular environment, Cu2+ ions are reduced to Cu+ by endogenous GSH, which decreases the intracellular antioxidant capacity and additionally up-regulates ˙OH production via the Cu+-induced Fenton-like reaction. Moreover, under near-infrared light irradiation, the bimetallic nanoparticles display a photothermal conversion efficacy of 46.7%, which not only improves chemodynamic therapy via boosting a Fenton-like reaction but results in photothermal therapy through hyperthermia. Both in vitro cancer cell killing and in vivo tumor ablation experiments show that the bimetallic nanoparticles display outstanding therapeutic efficacy and negligible systemic toxicity, indicating their anticancer potential.

Co3O4 Nanoparticles Uniformly Dispersed in Rational Porous Carbon Nano-Boxes for Significantly Enhanced Electrocatalytic Detection of H2O2 Released from Living Cells.

A facile and ingenious method to chemical etching-coordinating a metal-organic framework (MOF) followed by an annealing treatment was proposed to prepare Co3O4 nanoparticles uniformly dispersed in rational porous carbon nano-boxes (Co3O4@CNBs), which was further used to detect H2O2 released from living cells. The Co3O4@CNBs H2O2 sensor delivers much higher sensitivity than non-etching/coordinating Co3O4, offering a limit of detection of 2.32 nM. The wide working range covers 10 nM-359 µM H2O2, while possessing good selectivity and excellent reproducibility. Moreover, this biosensor was used to successfully real-time detect H2O2 released from living cells, including both healthy and tumor cells. The excellent performance holds great promise for Co3O4@CNBs's applications in electrochemical biomimetic sensing, particularly real-time monitor H2O2 released from living cells.

Weak UVB Irradiation Promotes Macrophage M2 Polarization and Stabilizes Atherosclerosis.

Atherosclerosis (AS) is a chronic cardiovascular disease endangering human health and is one of the most common causes of myocardial infarction and stroke. Macrophage polarization plays a vital role in regulating plaque stability. As an important component of sunlight, ultraviolet B (UVB) has been proven to promote vitamin D and nitric oxide synthesis. This research used an AS model in ApoE-/- mice to study the effects of UVB on macrophage polarization and atherosclerotic plaque stability. In vitro, UVB irradiation increased arginase-I (Arg-I, M2 macrophage) and macrophage mannose receptor (CD206) expression, while the expression of inducible nitric oxide synthase (iNOS) (M1 macrophage) and CD86 was decreased. UVB promoted Akt phosphorylation in vitro. In vivo, UVB irradiation promoted the stabilization of atherosclerotic lesion plaques, while the phenotype of M2 macrophages increased. Our research provides new evidence for UVB in preventing and treating atherosclerosis.

Near-infrared light-triggered synergistic antitumor therapy based on hollow ZIF-67-derived Co3S4-indocyanine green nanocomplex as a superior reactive oxygen species generator.

Reactive oxygen species (ROS) with strong oxidability have been considered as effective agents for antitumor therapy through oxidative damage to lipids, proteins, DNA and RNA. In this work, a multifunctional hollow cobaltosic sulfide (Co3S4)/photosensitizer indocyanine green (ICG) nanocomplex (Co3S4-ICG) has been synthesized by efficiently loading ICG into the hollow Co3S4 to realize synergistic antitumor therapy via chemodynamic therapy (CDT), photodynamic therapy (PDT) and photothermal therapy (PTT) under near-infrared (808 nm) laser irradiation. Co3S4 nanoparticles would be degraded in tumor acidic microenvironment into Co2+, which locally triggers a Fenton-like reaction to produce cytotoxic hydroxyl radicals (OH) for CDT. Co3S4-ICG could also produce singlet oxygen (1O2) through a multi-step photochemical process for PDT under 808 nm laser irradiation. The slow release of ICG in the tumor region was achieved due to hollow-structured Co3S4 working as nanocarriers, and which has been proved an effective approach for combined CDT/PDT. In addition, Co3S4-ICG showed high photothermal conversion efficiency (40.5%) for PTT, and excellent OH generation capability via photothermal-improved Fenton reaction, leading to the synergistically improved antitumor efficacy. In vitro and in vivo experimental results confirm that the combined PTT/PDT/photothermal-enhanced CDT therapy can effectively ablate tumors with a negligible systemic toxicity. This work provides a valuable strategy for designing and constructing of a multifunctional nanoplatform for synergistic antitumor therapy of solid tumors.

Background-free cell surface glycan analysis using persistent luminescence nanoparticle as an optical probe.

In this work, we report a novel cell surface glycan analysis method based on persistent luminescence nanoparticle (PLNP) ZnGa2O4: Cr3+ (ZGC) as an optical probe. ZGC was first silanized by (3-Aminopropyl) triethoxysilane (APTES), followed by PEGylation with NHS-P EG-Biotin, which not only introduces biotin, but significantly improves the dispersibility and stability of the nanoparticles. Neutral-avidin was then coupled on ZGC surface through the specific biotin-avidin interaction, producing a ZGC-PEG-avidin nanoprobe. As for cell surface glycan detection, different surface glycans are recognized with their corresponding biotinylated lectins, which are then traced by ZGC-PEG-avidin. The persistent luminescence signal is recorded by a microtiter plate reader in time-resolved fluorescence mode. Glycans expression profiling on prostate cancer cell DU145 and normal prostate cell RWPE-1 was analyzed by the proposed detection platform. Similar results were observed from the conventional horseradish peroxidase (HRP)-catalyzed absorbent assay and confocal microscope-based fluorescence imaging, demonstrating the applicability of the proposed platform. The approach based on the long afterglow property of ZGC efficiently eliminates the background noise from cells and substrate, resulting in the best signal-to-noise ratio and high detection sensitivity.

Parallel study on protein O-GlcNAcylation in prostate cancer cell with a sensitive microarray biochip.

Although a variety of approaches have been developed to analyze protein O-GlcNAcylation, efficient investigations on O-GlcNAcylation of proteins of interest in high-throughput manner are still in high demand to further explore its functionality. In this work, we first develop a powerful microarray platform for a sensitive, specific and high-throughput analysis of protein O-GlcNAcylation. The developed array biochip is then utilized to parallelly analyze the O-GlcNAcylation of three oncogenic transcription factors C-Myc, NF-κB and p53 in normal prostate epithelial cell (RWPE-1) and prostate cancer cell line (PC-3). The levels of O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are also monitored by the microarray platform. The experimental results show that the overall O-GlcNAcylation and OGT expression level are obviously elevated in PC-3 as compared to RWPE-1. The protein expression-normalized O-GlcNAcylation of C-Myc and NF-κB in PC-3 is significantly higher than that in RWPE-1, while opposite result is observed from p53. In addition, the biological behaviors including proliferation and migration of PC-3 cells are also studied when OGA inhibitor Thiamet G is applied to elevate the total O-GlcNAcylation level.

FePO4 embedded in nanofibers consisting of amorphous carbon and reduced graphene oxide as an enzyme mimetic for monitoring superoxide anions released by living cells.

FePO4 is biocompatible and can act as a kind of promising enzyme mimetic. Unfortunately, the electrical conductivity of FePO4 is poor. In order to enhance its conductivity, FePO4 was embedded into nanofibers consisting of amorphous carbon and reduced graphene oxide (rGO) by an electrospinning technique. As a sensing material for monitoring superoxide anion (O2•-) and typically operated at 0.5 V (vs. SCE), it displays high sensitivity (9.6 µA⋅µM-1⋅cm-2), a low detection limit (9.7 nM at S/N = 3), a wide linear response range (10 nM to 10 µM), and fast response (1.6 s). Due to its low detection limit and fast response, the sensor in our perception has a large potential for detecting superoxide anions released by HeLa cancer cells. Graphical abstract Schematic of the microstructure of FePO4/C and FePO4/rGO-C nanofibers, a photograph of cancer cells (HeLa), and the electrochemical response towards O2-• of the sensor.