Flexocatalysis Enhances Tumor Photodynamic Therapy.

Photodynamic therapy (PDT) is long-standing suffered from elevated tumor interstitial fluid pressure (TIFP) and prevalent hypoxic microenvironment within the solid malignancies. Herein, sound-activated flexocatalysis is developed to overcome the dilemma of PDT through both enhancing tumor penetration of photosensitizers by reducing TIFP and establishing an oxygen-rich microenvironment. In detail, a Schottky junction is constructed by flexocatalyst MoSe2 nanoflowers and Pt. Subsequently, the Schottky junction is loaded with the photosensitizer indocyanine green (ICG) and encapsulated within tumor cytomembrane to constitute a bionic-flexocatalytic nanomedicine (MPI@M). After targeting the tumor, MPI@M orchestrates flexocatalytic water splitting in tumor interstitial fluid under acoustic stimulation to lower TIFP, which boosted the tumor penetration of ICG. Concurrently, the oxygen released from the flexocatalytic water splitting overcomes the limitation of hypoxia against PDT. Furthermore, superfluous singlet oxygen generated by PDT can induce mitochondrial dysfunction for further tumor cell apoptosis. After 60 min of flexocatalysis, both the 30% decrease of TIFP and the relieved tumor hypoxia are observed, significantly promoting the therapeutic effect of PDT. Consequently, MoSe2/Pt junction nanoflowers, with the excellent flexocatalytic performance, hold significant potential for future applications in biocatalytic cancer therapies.

1,3,6-Trigalloylglucose: A Novel Potent Anti-Helicobacter pylori Adhesion Agent Derived from Aqueous Extracts of Terminalia chebula Retz.

1,3,6-Trigalloylglucose is a natural compound that can be extracted from the aqueous extracts of ripe fruit of Terminalia chebula Retz, commonly known as "Haritaki". The potential anti-Helicobacter pylori (HP) activity of this compound has not been extensively studied or confirmed in scientific research. This compound was isolated using a semi-preparative liquid chromatography (LC) system and identified through Ultra-high-performance liquid chromatography-MS/MS (UPLC-MS/MS) and Nuclear Magnetic Resonance (NMR). Its role was evaluated using Minimum inhibitory concentration (MIC) assay and minimum bactericidal concentration (MBC) assay, scanning electron microscope (SEM), inhibiting kinetics curves, urea fast test, Cell Counting Kit-8 (CCK-8) assay, Western blot, and Griess Reagent System. Results showed that this compound effectively inhibits the growth of HP strain ATCC 700392, damages the HP structure, and suppresses the Cytotoxin-associated gene A (Cag A) protein, a crucial factor in HP infection. Importantly, it exhibits selective antimicrobial activity without impacting normal epithelial cells GES-1. In vitro studies have revealed that 1,3,6-Trigalloylglucose acts as an anti-adhesive agent, disrupting the adhesion of HP to host cells, a critical step in HP infection. These findings underscore the potential of 1,3,6-Trigalloylglucose as a targeted therapeutic agent against HP infections.

Identification of the novel exhausted T cell CD8 + markers in breast cancer.

Cancer is one of the most concerning public health issues and breast cancer is one of the most common cancers in the world. The immune cells within the tumor microenvironment regulate cancer development. In this study, single immune cell data sets were used to identify marker gene sets for exhausted CD8 + T cells (CD8Tex) in breast cancer. Machine learning methods were used to cluster subtypes and establish the prognostic models with breast cancer bulk data using the gene sets to evaluate the impacts of CD8Tex. We analyzed breast cancer overexpressing and survival-associated marker genes and identified CD8Tex hub genes in the protein-protein-interaction network. The relevance of the hub genes for CD8 + T-cells in breast cancer was evaluated. The clinical associations of the hub genes were analyzed using bulk sequencing data and spatial sequencing data. The pan-cancer expression, survival, and immune association of the hub genes were analyzed. We identified biomarker gene sets for CD8Tex in breast cancer. CD8Tex-based subtyping systems and prognostic models performed well in the separation of patients with different immune relevance and survival. CRTAM, CLEC2D, and KLRB1 were identified as CD8Tex hub genes and were demonstrated to have potential clinical relevance and immune therapy impact. This study provides a unique view of the critical CD8Tex hub genes for cancer immune therapy.

Voltage-gated sodium channels in cancers.

Voltage-gated sodium channels (VGSCs) initiate action potentials in electrically excitable cells and tissues. Surprisingly, some VGSC genes are aberrantly expressed in a variety of cancers, derived from "non-excitable" tissues that do not generate classic action potentials, showing potential as a promising pharmacological target for cancer. Most of the previous review articles on this topic are limited in scope, and largely unable to provide researchers with a comprehensive understanding of the role of VGSC in cancers. Here, we review the expression patterns of all nine VGSC α-subunit genes (SCN1A-11A) and their four regulatory ß-subunit genes (SCN1B-4B). We reviewed data from the Cancer Genome Atlas (TCGA) database, complemented by an extensive search of the published papers. We summarized and reviewed previous independent studies and analyzed the VGSC genes in the TCGA database regarding the potential impact of VGSC on cancers. A comparison between evidence gathered from independent studies and data review was performed to scrutinize potential biases in prior research and provide insights into future research directions. The review supports the view that VGSCs play an important role in diagnostics as well as therapeutics of some cancer types, such as breast, colon, prostate, and lung cancer. This paper provides an overview of the current knowledge on voltage-gated sodium channels in cancer, as well as potential avenues for further research. While further research is required to fully understand the role of VGSCs in cancer, the potential of VGSCs for clinical diagnosis and treatment is promising.

Flexocatalytic Reduction of Tumor Interstitial Fluid/Solid Pressure for Efficient Nanodrug Penetration.

The practical efficacy of nanomedicines for treating solid tumors is frequently low, predominantly due to the elevated interstitial pressure within such tumors that obstructs the penetration of nanomedicines. This increased interstitial pressure originates from both liquid and solid stresses related to an undeveloped vascular network and excessive fibroblast proliferation. To specifically resolve the penetration issues of nanomedicines for tumor treatment, this study introduces a holistic "dual-faceted" approach. A treatment platform predicated on the WS2/Pt Schottky heterojunction was adopted, and flexocatalysis technology was used to disintegrate tumor interstitial fluids, thus producing oxygen and reactive oxygen species and effectively mitigating the interstitial fluid pressure. The chemotherapeutic agent curcumin was incorporated to further suppress the activity of cancer-associated fibroblasts, minimize collagen deposition in the extracellular matrix, and alleviate solid stress. Nanomedicines achieve homologous targeting by enveloping the tumor cell membrane. It was found that this multidimensional strategy not only alleviated the high-pressure milieu of the tumor interstitium─which enhanced the efficiency of nanomedicine delivery─but also triggered tumor cell apoptosis via the generated reactive oxygen species and modulated the tumor microenvironment. This, in turn, amplified immune responses, substantially optimizing the therapeutic impacts of nanomedicines.

Near-infrared-II photocharging nanozyme for enhanced tumor immunotherapy.

In tumor therapy, copper (Cu)-based nanozymes with peroxidase-like activity play a crucial role in converting hydrogen peroxide into hydroxyl radicals (OH). This process induces immunogenic cell death, which in turn activates the body's immune response, enhancing the efficacy of tumor immunotherapy. Nonetheless, the efficiency of this reaction is curtailed due to the oxidation of Cu(I) to Cu(II), leading to the self-depletion of the nanozyme's activity and an insufficient yield of OH for effective immunotherapeutic activation. To surmount this challenge, our research introduces a photocharging self-doped semiconductor nanozyme, copper sulfide (Cu9S8). The photocharging effect enables the nanozyme to convert internal Cu(II) back to Cu(I) through charge transfer induced by near-infrared (NIR)-II photothermal energy, thereby effectively maintaining the enzyme-like activity of the nanozyme. Additionally, Cu9S8 is enhanced with a calcium sulfide (CaS) coating. This coating reacts in the acidic microenvironment of tumors to generate hydrogen sulfide (H2S) gas, which in turn suppresses the catalase activity inherent in tumor cells, ensuring a plentiful supply of H2O2 for the nanozyme's operation. This dual strategy of amplifying enzyme-like activity and substrate availability culminates in the generation of ample OH within tumor cells, leading to significant immunogenic cell death and thereby realizing potent immunotherapy.

APR-246 increases tumor antigenicity independent of p53.

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8+ T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.