Overexpression of FERM Domain Containing Kindlin 2 (FERMT2) in Fibroblasts Correlates with EMT and Immunosuppression in Gastric Cancer.

The mesenchymal feature, dominated by epithelial mesenchymal transition (EMT) and stromal cell activation, is one of the main reasons for the aggressive nature of tumors, yet it remains poorly understood. In gastric cancer (GC), the fermitin family homolog-2 (FERMT2) is involved in macrophage signaling, promoting migration and invasion. However, the function of FERMT2 in fibroblasts remains unclear. Here, we demonstrated that downregulation of FERMT2 expression can block EMT in GC cells by inhibiting fibroblast activation in vitro. Furthermore, we found that, in addition to the known pathways, fibroblast-derived FERMT2 promotes M2-like macrophage growth and that in human GC samples, there is a strong positive correlation between FERMT2 and CD163 and CD206 levels. Notably, high FERMT2 expression was significantly associated with poor clinical outcomes and was upregulated in patients with advanced disease. Taken together, our results provide evidence that the fibroblast-FERMT2-EMT-M2 macrophage axis plays a critical role in the GC mesenchymal phenotype and may be a promising target for the treatment of advanced GC.

A novel pH-activated AIEgen probe for dynamic lysosome tracking and high-efficiency photodynamic therapy.

A novel AIEgen molecular probe (N-3QL) with typical AIE effects, good biocompatibility, lysosome targeting, pH activation, excellent photostability, and high brightness was synthesized using two simple synthetic steps. Spectroscopic and cytotoxicity experiments indicate that N-3QL can not only be used for the dynamic monitoring of cancer cell lysosomes, but also for photodynamic therapy (PDT) ablation of cancer cells.

A novel AIEgen photosensitizer with an elevated intersystem crossing rate for tumor precise imaging and therapy.

Herein, we have designed and synthesized a quinolinyl-AIE photosensitizer (TPE-4QL+) with an alternative elevated intersystem crossing (ISC) rate, which exhibits not only highly efficient photosensitivity but also high tumor cell specificity and an excellent mitochondrial targeting ability. In vitro experiments indicate that using TPE-4QL+ as a photosensitizer can induce a series of tumor cells to die with a low dose of radiation, but with no obvious toxicity to normal cells. The in vivo studies on a mouse model bearing a subcutaneous 4T1 xenograft also show that TPE-4QL+ can be used with high efficiency as a photosensitizer in PDT.

Tannic Acid-Assisted Biomineralization Strategy for Encapsulation and Intracellular Delivery of Protein Drugs.

Protein therapy has been considered to be one of the most direct and safe ways to regulate cell function and treat tumors. However, safe and effective intracellular delivery of protein drugs is still a key challenge. Herein, we developed a tannic acid-assisted biomineralization strategy for the encapsulation and intracellular delivery of protein drugs. RNase A and glucose oxidase (GOD) were choose as the protein drug model. RNase A, GOD, TA, and Mn2+ are mixed in one pot to attain RG@MT, and CaCO3 coating is subsequently carried out to construct RG@MT@C through biomineralization. Once RG@MT@C is endocytosed, the acidic environment of the lysosome will dissolve the protective layer of CaCO3 and produce plenty of CO2 to cause lysosome bursting, ensuring the lysosome escape of the RG@MT@C and thus releasing the generated TA-Mn2+, RNase A, and GOD into the cytoplasm. The released substances would activate starvation therapy, chemodynamic therapy, and protein therapy pathways to ensure a high performance of cancer therapy. Due to simple preparation, low toxicity, and controlled release in the tumor microenvironment, we expect it can realize efficient and nondestructive delivery of protein drugs and meet the needs for precise, high performance of synergistically antitumor therapy in biomedical applications.

Microemulsion-Confined Assembly of Magnetic Nanoclusters for pH/H2O2 Dual-Responsive T2-T1 Switchable MRI.

In this work, a T2-T1 switchable superparamagnetic iron oxide nanoprobe with a pH/H2O2 dual response was obtained using a microemulsion method. This novel method for the controllable assembly of small iron clusters followed by their independent modification was reported, which could not be prepared by common synthetic methods. The size of the assembled nanoprobe was uniform and controllable, with a stable T2 magnetic resonance imaging (MRI) signal under a single condition. When the nanoprobe was exposed to the tumor environment, the higher H+ and H2O2 concentrations at the tumor site could dissociate the nanoprobe and redisperse into small iron clusters. When this occurred, the T2 MRI signal was converted into a T1 MRI signal, achieving specific detection of tumors by a pH/H2O2 dual-response T2-T1 MRI.

Prognostic Value of LHFPL Tetraspan Subfamily Member 6 (LHFPL6) in Gastric Cancer: A Study Based on Bioinformatics Analysis and Experimental Validation.

PURPOSE: The identification of biomarkers and effective therapeutic targets for gastric cancer (GC), the most common cause of cancer-related deaths around the world, is currently a major focus in research. Here, we examined the utility of LHFPL6 as a prognostic biomarker and therapeutic target for GC. METHODS: We explored the clinical relevance, function, and molecular role of LHFPL6 in GC using the MethSurv, cBioPortal, TIMER, Gene Expression Profiling Interactive Analysis, ONCOMINE, MEXPRESS, and EWAS Atlas databases. The GSE118919, GSE29272, and GSE13861 datasets were used for differential expression analysis. Using The Cancer Genome Atlas, we developed a Cox regression model and assessed the clinical significance of LHFPLs. In addition, we used the "CIBERSORT" algorithm to make reliable immune infiltration estimations. Western blot and immunohistochemistry were used to examine protein expression. Cell migration and invasion were assessed using transwell experiments. THP-1-derived macrophages and GC cells were co-cultured in order to model tumor-macrophage interactions in vitro. The levels of CD206 and CD163 were measured using immunofluorescence assays. The results were visualized with the "ggplot2" and "circlize" packages. RESULTS: Our results showed that in GC, LHFPL6 overexpression was significantly associated with a poor prognosis. Our findings also suggested that LHFPL6 may be involved in the activation of the epithelial-mesenchymal transition. Furthermore, LHFPL6 expression showed a positive correlation with the abundance of M2 macrophages, which are potent immunosuppressors. CONCLUSION: LHFPL6 could be a prognostic biomarker and therapeutic target for GC.

Synergistically enhanced multienzyme catalytic nanoconjugates for efficient cancer therapy.

Tumors are complex and highly variable, making it difficult for a single treatment strategy to be significantly effective for cancer therapy. Herein, we report a robust cascade biomimetic nanoplatform that integrates chemiluminescence-induced photodynamic therapy (CL-PDT), Fenton reaction-based chemodynamic therapy (CDT), and glucose oxidase (GOD)-mediated starvation therapy to synergistically enhance cancer treatment. For the nanoplatform of CPPO@porphyrin-MOF@Cancer cell membrane-GOD (C1@M@C2G), the ferric ion-linked porphyrin-MOF can trigger a Fenton reaction to reach CDT, the carried CPPO as an energy donor is used to excite a photo-sensitive porphyrin-MOF in situ to generate singlet oxygen (1O2) for PDT, GOD catalyzes glucose into H2O2 and gluconic acid to realize starvation therapy, and the cancer cell membrane wrapped onto the nanoparticle plays a key role in homologous targeting, which is conducive to achieving better therapeutic effects. Significantly, the porphyrin-MOF with catalase-like activity can generate O2 to effectively relieve tumor hypoxia, thereby enhancing the catalytic effect of GOD and the efficacy of PDT. Additionally, the produced H2O2 and gluconic acid can further improve the CPPO-H2O2-triggered CL-PDT and promote the low pH-dependence Fenton reaction-based CDT, respectively. Both in vitro and in vivo studies showed that the constructed nanoplatform displays an excellent cooperative anti-tumor performance, so we firmly believe that this simple nanoplatform broadens the pathway to fight against cancer through effective cascade catalysis.

Self-Illuminated, Oxygen-Supplemented Photodynamic Therapy via a Multienzyme-Mimicking Nanoconjugate.

Current photodynamic therapy (PDT) faces several intrinsic limitations, including insufficient oxygen supply and limited penetration of external light sources. Herein, we report a nanoconjugate, which, in response to the elevated hydrogen peroxide levels associated with tumor tissues, can supplement the oxygen needed for PDT and provide local self-illumination. Consisting of a MnFe2O4 core, a metal-organic framework shell loaded with the chemiluminescence reagent luminol, and a hyaluronic acid surface coating, the nanoconjugate is highly effective for suppressing cancer tissues in vivo via PDT in the absence of externally delivered light.

Ultrathin two-dimensional covalent organic framework nanoprobe for interference-resistant two-photon fluorescence bioimaging.

The complex environment of living organisms significantly challenges the selectivity of classic small-molecule fluorescent probes for bioimaging. Due to their predesigned topological structure and engineered internal pore surface, covalent organic frameworks (COFs) have the ability to filter out coexisting interference components and help to achieve accurate biosensing. Herein, we propose an effective interference-resistant strategy by creating a COF-based hybrid probe that combines the respective advantages of COFs and small-molecule probes. As a proof of concept, a two-photon fluorescent COF nanoprobe, namely TpASH-NPHS, is developed for targeting hydrogen sulfide (H2S) as a model analyte. TpASH-NPHS exhibits limited cytotoxicity, excellent photostability and long-term bioimaging capability. More importantly, compared with the small-molecule probe, TpASH-NPHS achieves accurate detection without the interference from intracellular enzymes. This allows us to monitor the levels of endogenous H2S in a mouse model of cirrhosis.

Supramolecular assembly affording a ratiometric two-photon fluorescent nanoprobe for quantitative detection and bioimaging.

Fluorescence quantitative analyses for vital biomolecules are in great demand in biomedical science owing to their unique detection advantages with rapid, sensitive, non-damaging and specific identification. However, available fluorescence strategies for quantitative detection are usually hard to design and achieve. Inspired by supramolecular chemistry, a two-photon-excited fluorescent supramolecular nanoplatform (TPSNP) was designed for quantitative analysis with three parts: host molecules (ß-CD polymers), a guest fluorophore of sensing probes (Np-Ad) and a guest internal reference (NpRh-Ad). In this strategy, the TPSNP possesses the merits of (i) improved water-solubility and biocompatibility; (ii) increased tissue penetration depth for bioimaging by two-photon excitation; (iii) quantitative and tunable assembly of functional guest molecules to obtain optimized detection conditions; (iv) a common approach to avoid the limitation of complicated design by adjustment of sensing probes; and (v) accurate quantitative analysis by virtue of reference molecules. As a proof-of-concept, we utilized the two-photon fluorescent probe NHS-Ad-based TPSNP-1 to realize accurate quantitative analysis of hydrogen sulfide (H2S), with high sensitivity and good selectivity in live cells, deep tissues and ex vivo-dissected organs, suggesting that the TPSNP is an ideal quantitative indicator for clinical samples. What's more, TPSNP will pave the way for designing and preparing advanced supramolecular sensors for biosensing and biomedicine.