RESUMEN
Breakthroughs in actual clinical applications have begun through vaccine-based cancer immunotherapy, which uses the body's immune system, both humoral and cellular, to attack malignant cells and fight diseases. However, conventional vaccine approaches still face multiple challenges eliciting effective antigen-specific immune responses, resulting in immunotherapy resistance. In recent years, biomimetic nanovaccines have emerged as a promising alternative to conventional vaccine approaches by incorporating the natural structure of various biological entities, such as cells, viruses, and bacteria. Biomimetic nanovaccines offer the benefit of targeted antigen-presenting cell (APC) delivery, improved antigen/adjuvant loading, and biocompatibility, thereby improving the sensitivity of immunotherapy. This review presents a comprehensive overview of several kinds of biomimetic nanovaccines in anticancer immune response, including cell membrane-coated nanovaccines, self-assembling protein-based nanovaccines, extracellular vesicle-based nanovaccines, natural ligand-modified nanovaccines, artificial antigen-presenting cells-based nanovaccines and liposome-based nanovaccines. We also discuss the perspectives and challenges associated with the clinical translation of emerging biomimetic nanovaccine platforms for sensitizing cancer cells to immunotherapy.
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Células Presentadoras de Antígenos , Vacunas contra el Cáncer , Inmunoterapia , Nanopartículas , Neoplasias , Humanos , Neoplasias/terapia , Neoplasias/inmunología , Inmunoterapia/métodos , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Nanopartículas/administración & dosificación , Células Presentadoras de Antígenos/inmunología , Biomimética/métodos , Materiales Biomiméticos/administración & dosificación , Animales , Liposomas , NanovacunasRESUMEN
Ovarian cancer (OVC) is one of the most aggressive gynecological malignancies worldwide. Although olaparib treatment has shown favorable outcomes against the treatment of OVC, its effectiveness remains limited in some OVC patients. Investigating new strategies to improve the therapeutic efficacy of olaparib against OVC is imperative. Our study identified tabersonine, a natural indole alkaloid, for its potential to increase the chemosensitivity of olaparib in OVC. The combined treatment of olaparib and tabersonine synergistically inhibited cell proliferation in OVC cells and suppressed tumor growth in A2780 xenografts. The combined treatment effectively suppressed epithelial-mesenchymal transition (EMT) by altering the expression of E-cadherin, N-cadherin, and vimentin and induced DNA damage responses. Integrating quantitative proteomics, FHL1 was identified as a potential regulator to modulate EMT after tabersonine treatment. Increased expression of FHL1 was induced by tabersonine treatment, while downregulation of FHL1 reversed the inhibitory effects of tabersonine on OVC cells by mediating EMT. In vivo findings further reflected that the combined treatment of tabersonine and olaparib significantly inhibited tumor growth and OVC metastasis through upregulation of FHL1. Our findings reveal the role of tabersonine in improving the sensitivity of olaparib in OVC through FHL1-mediated EMT, suggesting that tabersonine holds promise for future application in OVC treatment.
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Transición Epitelial-Mesenquimal , Péptidos y Proteínas de Señalización Intracelular , Proteínas con Dominio LIM , Proteínas Musculares , Neoplasias Ováricas , Ftalazinas , Piperazinas , Animales , Femenino , Humanos , Ratones , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Alcaloides Indólicos/farmacología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Musculares/metabolismo , Proteínas Musculares/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Ftalazinas/farmacología , Piperazinas/farmacología , Quinolinas/farmacologíaRESUMEN
Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.
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Antineoplásicos , Neoplasias de la Mama , Indazoles , Macrófagos , Estructuras Metalorgánicas , Nanopartículas , Pirimidinas , Sulfonamidas , Animales , Femenino , Estructuras Metalorgánicas/química , Estructuras Metalorgánicas/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Humanos , Macrófagos/efectos de los fármacos , Indazoles/farmacología , Indazoles/química , Ratones , Pirimidinas/farmacología , Pirimidinas/química , Línea Celular Tumoral , Nanopartículas/química , Sulfonamidas/farmacología , Sulfonamidas/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ratones Endogámicos BALB C , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Environmental pollution, including air pollution, plastic contamination, and heavy metal exposure, is a pressing global issue. This crisis contributes significantly to pollution-related diseases and is a critical risk factor for chronic health conditions, including cancer. Mounting evidence underscores the pivotal role of N6-methyladenosine (m6A) as a crucial regulatory mechanism in pathological processes and cancer progression. Governed by m6A writers, erasers, and readers, m6A orchestrates alterations in target gene expression, consequently playing a vital role in a spectrum of RNA processes, covering mRNA processing, translation, degradation, splicing, nuclear export, and folding. Thus, there is a growing need to pinpoint specific m6A-regulated targets in environmental pollutant-induced carcinogenesis, an emerging area of research in cancer prevention. This review consolidates the understanding of m6A modification in environmental pollutant-induced tumorigenesis, explicitly examining its implications in lung, skin, and bladder cancer. We also investigate the biological mechanisms that underlie carcinogenesis originating from pollution. Specific m6A methylation pathways, such as the HIF1A/METTL3/IGF2BP3/BIRC5 network, METTL3/YTHDF1-mediated m6A modification of IL 24, METTL3/YTHDF2 dynamically catalyzed m6A modification of AKT1, METTL3-mediated m6A-modified oxidative stress, METTL16-mediated m6A modification, site-specific ATG13 methylation-mediated autophagy, and the role of m6A in up-regulating ribosome biogenesis, all come into play in this intricate process. Furthermore, we discuss the direction regarding the interplay between pollutants and RNA metabolism, particularly in immune response, providing new information on RNA modifications for future exploration.
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Adenosina , Carcinogénesis , Contaminantes Ambientales , Animales , Humanos , Adenosina/análogos & derivados , Carcinogénesis/inducido químicamente , Contaminantes Ambientales/toxicidad , ARN/genética , Metilación de ARNRESUMEN
CONTEXT: Cholangiocarcinoma with highly heterogeneous, aggressive, and multidrug resistance has a poor prognosis. Although babaodan (BBD) combined with cisplatin improved non-small cell lung cancer efficacy, its impact on overcoming resistance in cholangiocarcinoma remains unexplored. OBJECTIVE: This study explored the role and mechanism of BBD on cisplatin resistance in cholangiocarcinoma cells (CCAs). MATERIALS AND METHODS: Cisplatin-resistant CCAs were exposed to varying concentrations of cisplatin (25-400 µg/mL) or BBD (0.25-1.00 mg/mL) for 48 h. IC50 values, inhibition ratios, apoptosis levels, DNA damage, glutathione (GSH) levels, oxidized forms of GSH, total GSH content, and glutaminase relative activity were evaluated using the cell counting kit 8, flow cytometry, comet assay, and relevant assay kits. RESULTS: BBD-reduced the cisplatin IC50 in CCAs from 118.8 to 61.83 µg/mL, leading to increased inhibition rate, apoptosis, and DNA damage, and decreased expression of B-cell lymphoma-2, p-Yes-associated protein 1/Yes-associated protein 1, solute carrier family 1 member 5, activating transcription factor 4, and ERCC excision repair 1 in a dose-dependent manner with maximum reductions of 78.97%, 51.98%, 54.03%, 56.59%, and 63.22%, respectively; bcl2-associated X and gamma histone levels were increased by 0.43-115.77% and 22.15-53.39%. The impact of YAP1 knockdown on cisplatin-resistant CCAs resembled BBD. GSH, oxidized GSH species, total GSH content, and glutaminase activity in cisplatin-resistant CCAs with BBD treatment also decreased, while YAP1 overexpression countered BBD's effects. DISCUSSION AND CONCLUSION: This study provides a scientific basis for BBD clinical application and provides a new direction for BBD biological mechanism research.
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Antineoplásicos , Neoplasias de los Conductos Biliares , Carcinoma de Pulmón de Células no Pequeñas , Colangiocarcinoma , Neoplasias Pulmonares , Humanos , Cisplatino/farmacología , Proteínas Señalizadoras YAP , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Glutaminasa/metabolismo , Glutaminasa/farmacología , Glutaminasa/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Factores de Transcripción/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Colangiocarcinoma/tratamiento farmacológico , Colangiocarcinoma/genética , Colangiocarcinoma/patología , Neoplasias de los Conductos Biliares/tratamiento farmacológico , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Resistencia a Antineoplásicos , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular TumoralRESUMEN
CONTEXT: Tabersonine has been investigated for its role in modulating inflammation-associated pathways in various diseases. However, its regulatory effects on triple-negative breast cancer (TNBC) have not yet been fully elucidated. OBJECTIVE: This study uncovers the anticancer properties of tabersonine in TNBC cells, elucidating its role in enhancing chemosensitivity to cisplatin (CDDP). MATERIALS AND METHODS: After tabersonine (10 µM) and/or CDDP (10 µM) treatment for 48 h in BT549 and MDA-MB-231 cells, cell proliferation was evaluated using the cell counting kit-8 and colony formation assays. Quantitative proteomics, online prediction tools and molecular docking analyses were used to identify potential downstream targets of tabersonine. Transwell and wound-healing assays and Western blot analysis were used to assess epithelial-mesenchymal transition (EMT) phenotypes. RESULTS: Tabersonine demonstrated inhibitory effects on TNBC cells, with IC50 values at 48 h being 18.1 µM for BT549 and 27.0 µM for MDA-MB-231. The combined treatment of CDDP and tabersonine synergistically suppressed cell proliferation in BT549 and MDA-MB-231 cells. Enrichment analysis revealed that the proteins differentially regulated by tabersonine were involved in EMT-related signalling pathways. This combination treatment also effectively restricted EMT-related phenotypes. Through the integration of online target prediction and proteomic analysis, Aurora kinase A (AURKA) was identified as a potential downstream target of tabersonine. AURKA expression was reduced in TNBC cells post-treatment with tabersonine. DISCUSSION AND CONCLUSIONS: Tabersonine significantly enhances the chemosensitivity of CDDP in TNBC cells, underscoring its potential as a promising therapeutic agent for TNBC treatment.
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Aurora Quinasa A , Cisplatino , Transición Epitelial-Mesenquimal , Alcaloides Indólicos , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Antineoplásicos/farmacología , Aurora Quinasa A/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Sinergismo Farmacológico , Transición Epitelial-Mesenquimal/efectos de los fármacos , Alcaloides Indólicos/farmacología , Simulación del Acoplamiento Molecular , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Natural compounds are widely used to prevent and treat various diseases due to their antioxidant and anti-inflammatory effects. As a kind of promising natural compound, plant-derived exosome-like nanoparticles (PELNs) are extracted from multivesicular bodies of various edible plants, including vegetables, foods, and fruits, and mainly regulate the cellular immune response to pathogen attacks. Moreover, PELNs could remarkably interfere with the dynamic imbalance between pro-inflammatory and anti-inflammatory effects, facilitating to maintain the homeostasis of cellular immune microenvironment. PELNs may serve as a better alternative to animal-derived exosomes (ADEs) owing to their widespread sources, cost-effectiveness, and easy accessibility. PELNs can mediate interspecies communication by transferring various cargoes such as proteins, lipids, and nucleic acids from plant cells to mammalian cells. This review summarizes the biogenesis, composition, and classification of exosomes; the common separation, purification, and characterization methods of PELNs, the potential advantages of PELNs over ADEs; and the anti-inflammatory and immunomodulatory functions of PELNs in various diseases including colitis, cancer, and inflammation-associated metabolic diseases. Additionally, the future perspectives of PELNs and the challenges associated with their clinical application are discussed.
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Exosomas , Nanopartículas , Neoplasias , Animales , Exosomas/metabolismo , Sistema Inmunológico/metabolismo , Plantas , Neoplasias/metabolismo , Mamíferos , Microambiente TumoralRESUMEN
BACKGROUND: The past few years have witnessed a significant increase in research related to plant-derived extracellular vesicles (PDEVs) in biological and medical applications. Using biochemical technologies, multiple independent groups have demonstrated the important roles of PDEVs as potential mediators involved in cell-cell communication and the exchange of bio-information between species. Recently, several contents have been well identified in PDEVs, including nucleic acids, proteins, lipids, and other active substances. These cargoes carried by PDEVs could be transferred into recipient cells and remarkably influence their biological behaviors associated with human diseases, such as cancers and inflammatory diseases. This review summarizes the latest updates regarding PDEVs and focuses on its important role in nanomedicine applications, as well as the potential of PDEVs as drug delivery strategies to develop diagnostic and therapeutic agents for the clinical management of diseases, especially like cancers. CONCLUSION: Considering its unique advantages, especially high stability, intrinsic bioactivity and easy absorption, further elaboration on molecular mechanisms and biological factors driving the function of PDEVs will provide new horizons for the treatment of human disease.
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Vesículas Extracelulares , Neoplasias , Humanos , Nanomedicina , Vesículas Extracelulares/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Sistemas de Liberación de Medicamentos , Comunicación CelularRESUMEN
Dihydroartemisinin (DHA), a natural product derived from the herbal medicine Artemisia annua, is recently used as a novel anti-cancer agent. However, some intrinsic disadvantages limit its potential for clinical management of cancer patients, such as poor water solubility and low bioavailability. Nowadays, the nanoscale drug delivery system emerges as a hopeful platform for improve the anti-cancer treatment. Accordingly, a metal-organic framework (MOF) based on zeolitic imidazolate framework-8 was designed and synthesized to carry DHA in the core (ZIF-DHA). Contrast with free DHA, these prepared ZIF-DHA nanoparticles (NPs) displayed preferable anti-tumor therapeutic activity in several ovarian cancer cells accompanied with suppressed production of cellular reactive oxygen species (ROS) and induced apoptotic cell death. 4D-FastDIA-based mass spectrometry technology indicated that down-regulated reactive oxygen species modulator 1 (ROMO1) might be regarded as potential therapeutic targets for ZIF-DHA NPs. Overexpression of ROMO1 in ovarian cancer cells significantly reversed the cellular ROS-generation induced by ZIF-DHA, as well as the pro-apoptosis effects. Taken together, our study elucidated and highlighted the potential of zeolitic imidazolate framework-8-based MOF to improve the activity of DHA to treat ovarian cancer. Our findings suggested that these prepared ZIF-DHA NPs could be an attractive therapeutic strategy for ovarian cancer.
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Estructuras Metalorgánicas , Nanopartículas , Neoplasias Ováricas , Humanos , Femenino , Especies Reactivas de Oxígeno , Neoplasias Ováricas/tratamiento farmacológico , Apoptosis , Proteínas de la Membrana , Proteínas MitocondrialesRESUMEN
Staging lymph nodes (LN) is crucial in diagnosing and treating cancer metastasis. Biotechnologies for the specific localization of metastatic lymph nodes (MLNs) have attracted significant attention to efficiently define tumor metastases. Bioimaging modalities, particularly magnetic nanoparticles (MNPs) such as iron oxide nanoparticles, have emerged as promising tools in cancer bioimaging, with great potential for use in the preoperative and intraoperative tracking of MLNs. As radiation-free magnetic resonance imaging (MRI) probes, MNPs can serve as alternative MRI contrast agents, offering improved accuracy and biological safety for nodal staging in cancer patients. Although MNPs' application is still in its initial stages, exploring their underlying mechanisms can enhance the sensitivity and multifunctionality of lymph node mapping. This review focuses on the feasibility and current application status of MNPs for imaging metastatic nodules in preclinical and clinical development. Furthermore, exploring novel and promising MNP-based strategies with controllable characteristics could lead to a more precise treatment of metastatic cancer patients.
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Nanopartículas de Magnetita , Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Fenómenos Físicos , Biotecnología , Ganglios Linfáticos/diagnóstico por imagenRESUMEN
RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer.
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Cromatina/metabolismo , Replicación del ADN , Proteínas Activadoras de GTPasa/fisiología , Factores de Intercambio de Guanina Nucleótido/fisiología , Proteína de Replicación A/metabolismo , Animales , Línea Celular Tumoral , Reparación del ADN , Femenino , Proteínas Activadoras de GTPasa/antagonistas & inhibidores , Proteínas Activadoras de GTPasa/metabolismo , Factores de Intercambio de Guanina Nucleótido/antagonistas & inhibidores , Factores de Intercambio de Guanina Nucleótido/metabolismo , Células HEK293 , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Fosforilación , Proteolisis , Transducción de Señal , Estrés Fisiológico/genética , Proteína de Unión al GTP cdc42/metabolismo , Quinasas p21 Activadas/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
PrimPol has been recently identified as a DNA damage tolerant polymerase that plays an important role in replication stress response. However, the regulatory mechanisms of PrimPol are not well defined. In this study, we identify that the deubiquitinase USP36 interferes with degradation of PrimPol to regulate the replication stress response. Mechanistically, USP36 is deubiquitinated following DNA replication stress, which in turn facilitates its upregulation and interaction with PrimPol. USP36 deubiquitinates K29-linked polyubiquitination of PrimPol and increases its protein stability. Depletion of USP36 results in replication stress-related defects and elevates cell sensitivity to DNA-damage agents, such as cisplatin and olaparib. Moreover, USP36 expression positively correlates with the level of PrimPol protein and poor prognosis in patient samples. These findings indicate that the regulation of PrimPol K29-linked ubiquitination by USP36 plays a critical role in DNA replication stress and chemotherapy response.
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ADN Primasa/genética , Replicación del ADN/efectos de los fármacos , ADN Polimerasa Dirigida por ADN/genética , Enzimas Multifuncionales/genética , Neoplasias Ováricas/genética , Ubiquitina Tiolesterasa/genética , Línea Celular Tumoral , Cisplatino/farmacología , Daño del ADN/efectos de los fármacos , Enzimas Desubicuitinizantes/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Ftalazinas/farmacología , Piperazinas/farmacología , Poliubiquitina/genética , Pronóstico , Estabilidad Proteica/efectos de los fármacos , Proteolisis/efectos de los fármacosRESUMEN
In the era of the rapid development of cancer immunotherapy, there is a high level of interest in the application of cell-released small vesicles that stimulate the immune system. As cell-derived nanovesicles, exosomes show great promise in cancer immunotherapy because of their immunogenicity and molecular transfer function. The cargoes carried on exosomes have been recently identified with improved technological advances and play functional roles in the regulation of immune responses. In particular, exosomes derived from tumor cells and immune cells exhibit unique composition profiles that are directly involved in anticancer immunotherapy. More importantly, exosomes can deliver their cargoes to targeted cells and thus influence the phenotype and immune-regulation functions of targeted cells. Accumulating evidence over the last decade has further revealed that exosomes can participate in multiple cellular processes contributing to cancer development and therapeutic effects, showing the dual characteristics of promoting and suppressing cancer. The potential of exosomes in the field of cancer immunotherapy is huge, and exosomes may become the most effective cancer vaccines, as well as targeted antigen/drug carriers. Understanding how exosomes can be utilized in immune therapy is important for controlling cancer progression; additionally, exosomes have implications for diagnostics and the development of novel therapeutic strategies. This review discusses the role of exosomes in immunotherapy as carriers to stimulate an anti-cancer immune response and as predictive markers for immune activation; furthermore, it summarizes the mechanism and clinical application prospects of exosome-based immunotherapy in human cancer.
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Vacunas contra el Cáncer/administración & dosificación , Portadores de Fármacos/química , Exosomas/química , Inmunidad/inmunología , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Animales , Vacunas contra el Cáncer/química , Humanos , Neoplasias/inmunologíaRESUMEN
Lung adenocarcinoma (LUAD) is the most common histological form of lung cancer that is clinically diagnosed. The aim of this study is to explore the novel genes associated with LUAD tumorigenesis. Comprehensive bioinformatics analyses of the data were obtained from several publicly available databases, such as the Gene Expression Omnibus, the Human Protein Atlas project, and the Cancer Cell Line Encyclopedia. The clinical relevance of these novel genes in LUAD was further examined by immunohistochemistry. We identified the overlapping differentially expressed genes (DEGs) in five independent microarray data sets from the Gene Expression Omnibus database ( GSE75037 , GSE85716 , GSE85841 , GSE63459 , and GSE32867 ). Using the criteria of |log (fold change)| ≥ 1 and P value <0.05, 167 genes were preliminarily validated as co-DEGs. Protein-protein interaction network analysis indicated that caveolin 1 (CAV1) and decorin (DCN) levels were significantly reduced and that these genes were the most promising predictive biomarkers for the occurrence and prognosis of LUAD. A cell proliferation assay indicated that overexpressed CAV1 and DCN could significantly inhibit the proliferation rate of A549 and H157 cells. Additionally, these two downregulated candidate genes were further verified by immunohistochemistry conducted on a LUAD tissue array and comprehensive bioinformatics analyses, including those using the Oncomine platform and the Cancer Cell Line Encyclopedia. Our study demonstrates low levels of CAV1 and DCN in LUAD. An understanding of their functional roles in LUAD biology would give us important insights that would be useful in further investigations.
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Adenocarcinoma del Pulmón/genética , Biomarcadores de Tumor/genética , Caveolina 1/genética , Decorina/genética , Neoplasias Pulmonares/genética , Células A549 , Adenocarcinoma del Pulmón/metabolismo , Biomarcadores de Tumor/metabolismo , Caveolina 1/metabolismo , Línea Celular Tumoral , Proliferación Celular , Biología Computacional , Decorina/metabolismo , Regulación hacia Abajo , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/metabolismo , Mapas de Interacción de Proteínas , Transducción de SeñalRESUMEN
BACKGROUND: Resistance to radiotherapy is one of the main obstacles to improving cancer prognoses. To effectively destroy cancer cells, novel radiation sensitizers are needed. Recently, several natural products have been shown to exhibit promising tumor-killing properties. However, little is known about the specific mechanisms of these natural compounds on cancer treatment. In this study, after screening a high-throughput natural product library, we identified tanshinone I (Tan I) as a potential radiation sensitizer in lung cancer cells. METHODS: Lung cancer radioresistant cell lines, H358-IR and H157-IR, were first established to confirm the radioresistant phenotypes. After that, a natural product library was used to screen the potential radiation sensitizer. We further examined the inhibition functions of Tan I on radioresistant cancer cells via a series of experiments. RESULTS: Tan I significantly inhibited cell proliferation and clone formation, consequently enhancing radiosensitivity in radioresistant lung cancer cells, H358-IR and H157-IR. Stable isotope labeling of amino acids in cell culture (SILAC)-based quantitative proteomics indicated that Tan I downregulates expression of pro-oncogenic protein phosphoribosyl pyrophosphate aminotransferase (PPAT) in both H358-IR and H157-IR cells. Further analysis of molecular docking showed that Tan I is well-docked into the active pocket of the structure of PPAT, serving as a potential PPAT inhibitor. CONCLUSIONS: Taken together, these findings suggest that inhibition of the tumor promoter PPAT by Tan I exerts marked inhibitory effects on radioresistant lung cancer cells, improving radiation efficacy.
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Abietanos/farmacología , Neoplasias Pulmonares/terapia , Tolerancia a Radiación/efectos de los fármacos , Fármacos Sensibilizantes a Radiaciones/farmacología , Transaminasas/antagonistas & inhibidores , Abietanos/química , Abietanos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Quimioradioterapia/métodos , Regulación hacia Abajo , Ensayos de Selección de Medicamentos Antitumorales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Neoplasias Pulmonares/patología , Simulación del Acoplamiento Molecular , Fármacos Sensibilizantes a Radiaciones/química , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Transaminasas/química , Transaminasas/metabolismoRESUMEN
OBJECTIVE: To explore the association of VEGFR2 gene polymorphisms (rs2305948 and rs1870377) with the effect of levodopa (L-dopa) and dyskinesia in Chinese population and to provide theoretical basis for clinical treatment.â© METHODS: By using Taqman MGB analysis and gene sequencing, the rs2305948 and rs1870377 polymorphisms of 69 enrolled Parkinson's disease (PD) patients were detected. Among them, 32 cases developed dyskinesia during 5 years and 37 cases did not develop dyskinesia during 8 years (as the control).â© RESULTS: There was no significant association between the occurrence of dyskinesia and VEGFR2 polymorphisms at rs2305948 and rs1870377. However, rs1870377 polymorphism of AA showed greater maximum L-dopa dose [(565.00±163.55) mg/d vs (396.88±200.39) mg/d, (300.00±80.18) mg/d, P=0.038] and higher value of Modified Abnormal Involuntary Movement Scale (mAIMS) compared with that with polymorphisms of AT and TT [17.00±5.24 vs 8.94±6.53, 7.86±4.45, P=0.026]. â© CONCLUSION: VEGFR2 genes polymorphism (rs1870377) is associated with maximum L-dopa dose and mAIMS value in PD patients.
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Antiparkinsonianos/farmacología , Levodopa/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Polimorfismo Genético , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Humanos , Enfermedad de Parkinson/genéticaRESUMEN
BACKGROUND: Renal cell carcinoma (RCC) is a malignant tumor. Radix Actinidiae chinensis (RAC) is the root of Actinidia arguta (Sieb. et Zucc) Planch. ex Miq. In clinical research, RAC was confirmed to have a certain anti-tumor effect, including liver cancer and cholangiocarcinoma. This study investigated the anticancer effect and mechanism of RAC in RCC cells. METHODS: The 786-O and A498 cells were intervened with varying concentrations of RAC (0-100 mg/mL) to detect the half maximal inhibitory concentration (IC50) of RAC. The cells were then co-cultured with 0-50 mg/mL RAC for 0-72 h to assess the effect of RAC on cell viability using the cell counting kit-8. The effects on cell proliferation, cell cycle or apoptosis, migration or invasion, and autophagy were detected using cloning, flow cytometry, Transwell, AOPI assay and Western blot. The number of autophagolysosomes was quantified using a transmission electron microscope. PI3K/AKT/mTOR pathway-related proteins were detected by Western blot. Additionally, an autophagy inhibitor 3-MA was used to explore the underlying mechanism of RAC. RESULTS: IC50 values of RAC in 786-O and A498 were 14.76 mg/mL and 13.09 mg/mL, respectively. RAC demonstrated the ability to reduce the cell malignant phenotype of RCC cells, blocked the S phase of cells, promoted apoptosis and autophagy in cells. Furthermore, RAC was observed to increase autophagy-related proteins LC3II/I and Beclin-1, while decreasing the level of P62. The expression of apoptosis-related proteins was increased, while the ratios of p-PI3K/PI3K, p-AKT/AKT, p-mTOR/mTOR, p-P38/P38 and p-ERK/ERK were reduced by RAC. However, the addition of 3-MA reduced the apoptosis and autophagy- promotion effects of RAC on RCC cells. CONCLUSION: RAC induced the apoptosis and autophagy, to inhibit the progression of RCC cells. This study may provide a theoretical and experimental basis for clinical anti-cancer application of RAC for RCC.
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Apoptosis , Autofagia , Carcinoma de Células Renales , Proliferación Celular , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/metabolismo , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/metabolismo , Proliferación Celular/efectos de los fármacos , Actinidia/química , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Transducción de Señal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Supervivencia Celular/efectos de los fármacosRESUMEN
Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, such as Olaparib, have been pivotal in treating BRCA-deficient ovarian cancer. However, their efficacy is limited in over 40% of BRCA-deficient patients, with acquired resistance posing new clinical challenges. To address this, we employed bioinformatics methods to identify key genes impacting Olaparib sensitivity in ovarian cancer. Through comprehensive analysis of public databases including GEO, CPTAC, Kaplan Meier Plotter, and CCLE, we identified CRABP2 as significantly upregulated at both mRNA and protein levels in ovarian cancer, correlating with poor prognosis and decreased Olaparib sensitivity. Using colony formation and CCK-8 assays, we confirmed that CRABP2 knockdown in OVCAR3 and TOV112D cells enhanced sensitivity to Olaparib. Additionally, 4D label-free quantitative proteomics analysis, GSEA, and GO/KEGG analysis revealed CRABP2's involvement in regulating oxidation signals. Flow cytometry, colony formation assays, and western blotting demonstrated that CRABP2 knockdown promoted ROS production by activating Caspase-8, thereby augmenting Olaparib sensitivity and inhibiting ovarian cancer cell proliferation. Moreover, in xenograft models, CRABP2 knockdown significantly suppressed tumorigenesis and enhanced Olaparib sensitivity, with the effect being reversed upon Caspase-8 knockdown. These findings suggest that CRABP2 may modulate Olaparib sensitivity in ovarian cancer through the Caspase-8/ROS axis, highlighting its potential as a target for Olaparib sensitization.
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Neoplasias Ováricas , Ftalazinas , Piperazinas , Femenino , Humanos , Apoptosis , Caspasa 8/genética , Caspasa 8/metabolismo , Línea Celular Tumoral , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Ftalazinas/farmacología , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Poli(ADP-Ribosa) Polimerasas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Recent studies have discovered that tiny particles of microplastics (MPs) at the nano-scale level can enter the body of organisms from the environment, potentially causing metabolic ailments. However, further investigation is required to understand the alterations in the immune microenvironment associated with non-alcoholic fatty liver disease (NAFLD) occurrence following exposure to MPs. Experiments were performed using mice, which were given a normal chow or high-fat diet (NCD or HFD, respectively) plus free drinking of sterile water with or without MPs, respectively. Employing an impartial technique known as unbiased single-cell RNA-sequencing (scRNA-seq), the cellular (single-cell) pathology landscape of NAFLD and related changes in the identified immune cell populations induced following MPs plus HFD treatment were assessed. The results showed that mice in the HFD groups had remarkably greater NAFLD activity scores than those from the NCD groups. Moreover, administration of MPs plus HFD further worsened the histopathological changes in the mice's liver, leading to hepatic steatosis, inflammatory cell infiltrations and ballooning degeneration. Following the construction of a sing-cell resolution transcriptomic atlas of 43,480 cells in the mice's livers of the indicated groups, clear cellular heterogeneity and potential cell-to-cell cross-talk could be observed. Specifically, we observed that MPs exacerbated the pro-inflammatory response and influenced the stemness of hepatocytes during HFD feeding. Importantly, treatment with MPs significantly increase the infiltration of the infiltrating liver-protecting Vsig4+ macrophages in the liver of the NAFLD mouse model while remarkably decreasing the angiogenic S100A6+ macrophage subpopulation. Furthermore, mice treated with MPs plus HFD exhibited significantly increased recruitment of CD4+ cells and heightened exhaustion of CD8+ T cells than those from the control group, characteristics typically associated with the dysregulation of immune homeostasis and severe inflammatory damage. Overall, this study offers valuable perspectives into comprehending the potential underlying cellular mechanisms and regulatory aspects of the microenvironment regarding MPs in the development of NAFLD.
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Enfermedad del Hígado Graso no Alcohólico , Enfermedades no Transmisibles , Ratones , Animales , Microplásticos/metabolismo , Plásticos/metabolismo , Análisis de Expresión Génica de una Sola Célula , Hígado/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones Endogámicos C57BLRESUMEN
The cGAS-STING signaling pathway has emerged as a critical mediator of innate immune responses, playing a crucial role in improving antitumor immunity through immune effector responses. Targeting the cGAS-STING pathway holds promise for overcoming immunosuppressive tumor microenvironments (TME) and promoting effective tumor elimination. However, systemic administration of current STING agonists faces challenges related to low bioavailability and potential adverse effects, thus limiting their clinical applicability. Recently, nanotechnology-based strategies have been developed to modulate TMEs for robust immunotherapeutic responses. The encapsulation and delivery of STING agonists within nanoparticles (STING-NPs) present an attractive avenue for antitumor immunotherapy. This review explores a range of nanoparticles designed to encapsulate STING agonists, highlighting their benefits, including favorable biocompatibility, improved tumor penetration, and efficient intracellular delivery of STING agonists. The review also summarizes the immunomodulatory impacts of STING-NPs on the TME, including enhanced secretion of pro-inflammatory cytokines and chemokines, dendritic cell activation, cytotoxic T cell priming, macrophage re-education, and vasculature normalization. Furthermore, the review offers insights into co-delivered nanoplatforms involving STING agonists alongside antitumor agents such as chemotherapeutic compounds, immune checkpoint inhibitors, antigen peptides, and other immune adjuvants. These platforms demonstrate remarkable versatility in inducing immunogenic responses within the TME, ultimately amplifying the potential for antitumor immunotherapy.