DNA Tetrahedron-Driven Multivalent Proteolysis-Targeting Chimeras: Enhancing Protein Degradation Efficiency and Tumor Targeting

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

Proteolysis-targeting chimeras (PROTACs) are dual-functional molecules composed of a protein interest (POI) ligand and an E3 ligase connected by linker, which can recruit POI ligases simultaneously, thereby inducing the degradation showing great potential in disease treatment. A challenge developing PROTACs is design linkers modification ligands to establish multifunctional platform that enhances efficiency antitumor activity. As programmable modifiable nanomaterial, DNA tetrahedron precisely assemble selectively recognize flexibly adjust distance between molecules, making them ideal linkers. Herein, we developed multivalent PROTAC based on tetrahedron, named AS-TD2-PRO. Using as combined modules targeting tumor cells, recognizing ligases, multiple together. We took undruggable target signal transducer activator transcription 3 (STAT3), associated with etiology progression variety malignant tumors, example this study. AS-TD2-PRO two STAT3 recognition demonstrated good enhancing tumor-specific compared traditional bivalent PROTACs. Furthermore, mouse model, superior therapeutic activity was observed. Overall, tetrahedron-driven both serve proof principle for introduce promising avenue cancer treatment strategies.

Язык: Английский

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Constructing a Prognostic Model for Subtypes of Colorectal Cancer Based on Machine Learning and Immune Infiltration‐Related Genes

Journal of Cellular and Molecular Medicine, Год журнала: 2025, Номер 29(4)

Опубликована: Фев. 1, 2025

ABSTRACT This study constructed a prognostic model combining machine learning‐based immune infiltration‐related genes in each CRC subtype. We used publicly accessible gene expression data and clinical information on colorectal cancer patients. Integrated bioinformatics analysis was for the identification of immune‐wise genes. Machine learning algorithms, like LASSO regression random forest, were utilised to identify most important that may serve as predictors patient prognosis. Univariate Cox regression, consensus clustering well algorithms conducted construct risk scoring model. Analysis functional enrichment, infiltration analyses copy number variations mutational burdens performed validated at single‐cell level. A is designed with good predictive power—an area under receiver operating characteristic curve (AUC‐ROC) C‐index cross‐validation. The also achieved calibration discrimination ability stratify patients into high‐ low‐risk groups statistically significant difference OS ( p < 0.05). have integrated multiple types network features systems based characteristics integrating networks Multi‐Expense Learning we propose robust approach predicting molecular subtype survival. could potentially steer personalised treatment strategies ameliorate outcomes Although validation other cohorts situations necessary, it be useful.

Язык: Английский

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Dual‐Responsive PPy‐AIPH@LA Nanoplatform for Synergistic Photothermal and Thermodynamic Therapy of Colorectal Cancer

ChemistrySelect, Год журнала: 2025, Номер 10(10)

Опубликована: Март 1, 2025

Abstract In this study, we introduce a novel nanoplatform, polypyrrole (PPy)‐2,2′‐Azobis[2‐(2‐imidazolin‐2‐yl)propane] dihydrochloride (AIPH)@lauric acid (LA) (PPy‐AIPH@LA) nanoparticles (NPs), designed to overcome these limitations through synergistic photothermal therapy (PTT) and photodynamic (PDT). This dual‐responsive system incorporates PPy for efficient conversion, AIPH thermos‐responsive oxygen‐independent free radical generation, LA as thermally responsive encapsulation layer. The coating melts upon 808 nm near‐infrared laser irradiation, releasing radicals enable precise spatiotemporal activation of therapeutic effects. PPy‐AIPH@LA demonstrates exceptional conversion efficiency (55.74%) generates sufficient enhance PDT efficacy, even in hypoxic tumor microenvironments. vitro studies revealed concentration‐dependent cell ablation inhibition migration, while vivo experiments showed that the combined PTT‐PDT treatment achieved an impressive 90.7% growth rate mouse colon cancer cells CT‐26 murine model, with no significant systemic toxicity. Molecular analyses further modulations pathways associated metabolism, apoptosis, immune escape, highlighting comprehensive potential nanoplatform. These findings underscore safe, effective, minimally invasive nanotherapeutic platform combating CRC other solid tumors.

Язык: Английский

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Regulatory effect of Wnt signaling on mitochondria in cancer: from mechanism to therapy

APOPTOSIS, Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Cancer is one of the most significant public health challenges in new millennium, and complex mechanisms are at work to contribute its pathogenesis progression. The Wnt signaling pathways, which crucial conserved cascades involved embryological development tissue homeostasis, mitochondria, intracellular powerhouses responsible for energy production, calcium iron as well mitochondrial apoptosis eukaryotic cells, have their own regulating these pathological processes. In past decade, accumulating evidence has indicated that pathways directly regulate biogenesis function under physiological conditions. this review, we systemically summarize current understanding how particularly canonical cascade, fission, respiration, metabolism, mitochondrial-dependent cancer. addition, discuss recent advancements research anticancer agents related pharmacological targeting transduction pathway and/or function. We believe combined use pharmaceuticals mitochondria with conventional therapies, immunotherapy targeted therapy based on accurate molecular diagnosis will undoubtedly be future mainstream direction personalized cancer treatment, could benefit more patients.

Язык: Английский

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Causal impacts of 731 immunocyte phenotypes on colorectal cancer-evidence from a bidirectional two-sample Mendelian randomization

Human Vaccines & Immunotherapeutics, Год журнала: 2024, Номер 20(1)

Опубликована: Ноя. 25, 2024

Colorectal cancer is one of the most common and lethal malignancies, various factors have been confirmed to contribute its occurrence. However, causal role immune cell-specific changes in development colorectal has not investigated. The bidirectional two-sample Mendelian randomization analysis was performed explore association between 731 types cell phenotypes-specific cancer. inverse variance weighting results indicated that a total 31 28 phenotypes significantly associated with two different datasets, respectively. primary suggested BAFF-R on IgD+ CD38dim (OR = 1.033, 95%CI: 1.005-1.062) SSC-A monocyte 1.055, 1.016-1.096) served as risk factor for In addition, meta-analysis further supports link (pooled OR 1.035, 1.013-1.059) 1.060, 1.026-1.095) Finally, result genetic determinants may decrease level HLA DR++ absolute count 0.686, 0.508-0.925). Our potential identified cells be appealing drug targets cancer, but lack confirmation from real clinical evidence. Further studies are needed investigate roles these

Язык: Английский

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Decoding β-catenin associated protein-protein interactions: Emerging cancer therapeutic opportunities

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2024, Номер 1880(1), С. 189232 - 189232

Опубликована: Дек. 4, 2024

Язык: Английский

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