Браузер не даёт сохранять данные (например, приватный режим): закладки пропадут после закрытия вкладки.
Поиск статей PubMed
Ключевые слова, автор, журнал, годы — результаты из PubMed, аннотации с переводом на русский, закладки в браузере.
Найдено: 5 473
Страница 252 из 548-
[Ultrastructural characteristics of the craniopharyngoma (normal tumor, organotypical culture, before and after amethopterin)].
-
Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids.
Parechovirus ahumpari 3 (HPeV-3) is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.
-
CDK2/9 blockade remodels chromatin and drives phenotypic plasticity in glioblastoma organoids.
BACKGROUND: Glioblastoma (GBM) remains a highly lethal brain tumor with limited therapeutic options and pervasive resistance to standard treatments. Cyclin-dependent kinases (CDKs), key regulators of cell cycle progression and transcription, are frequently dysregulated in GBM and contribute to tumor pathogenesis. METHODS: We employed a range of preclinical GBM models-including 2D cultures, 3D spheroids, patient-derived organoids (PDOs), and multicellular 3D bioprints-to evaluate the effects of the CDK2/9 inhibitor fadraciclib in comparison to the standard-of-care temozolomide. Endpoints included cell viability, stress responses, immune-modulatory effects, and transcriptomic reprogramming. RESULTS: Fadraciclib robustly reduces cell viability and invasion in all patient-specific 2D- and 3D models. This effect was independent of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, demonstrating superior efficacy to temozolomide. Mechanistically, fadraciclib disrupted lysosomal, mitochondrial, and endoplasmic reticulum integrity and increased γH2AX levels, indicating enhanced DNA double-strand breaks. Seahorse analysis demonstrated impaired mitochondrial bioenergetics following fadraciclib treatment. In a triple-culture blood-brain barrier (BBB) model, fadraciclib demonstrated effective BBB penetration and antitumoral activity against GBM cells, while exhibiting minor cytotoxicity toward brain-specific normal cells. In semi-autologous co-culture systems, fadraciclib inhibited GBM invasion, promoted intercellular communication via Connexin 43 upregulation in microglia, and activated peripheral T cells. Transcriptomic analyses of treated patient-derived organoids revealed widespread transcriptional reprogramming, including downregulation of oncogenic long non-coding RNAs (MALAT1, POM121L9), suppression of immune-related pathways, and upregulation of the tumor suppressor LZTS1. Increased histone-associated gene expression suggests chromatin remodeling and induction of a quiescent tumor cell state. Subtype analysis indicated a shift toward a proneural molecular signature. Notably, the antitumoral effects of fadraciclib were preserved in multicellular biomimetic bioprints, whereas nonmalignant astrocytes and microglia were not affected. Therapeutic activity also coincided with altered secretion profiles of extracellular vesicles (EV). EVs from reactive astrocytes contained higher amounts of Fas, which may act as modulator of neuroinflammation. CONCLUSION: CDK2/9 inhibition shows promise as a therapeutic strategy for GBM. Fadraciclib exhibits multifaceted anti-tumor activity and spares nonmalignant cells of the central nervous system, supporting its further development in therapies that target transcriptional and immune pathways, as well as quiescent tumor cell populations.
-
Fast axonal transport: recent developments.
-
Biobanked Glioblastoma Patient-Derived Organoids as a Precision Medicine Model to Study Inhibition of Invasion.
Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.
-
Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids.
Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. Here, we used single-cell and cell type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GC exposure influenced lineage specification primarily by priming the inhibitory neuron lineage through transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.
-
Organoids in host pathology: Unveiling microbial-induced therapeutic responses.
Organoids are three-dimensional (3D) cultures derived from stem cells that replicate the complex structure and function of human tissues. They provide a physiologically relevant platform for studying microbial-host interactions, offering insights into pathogen-induced host lesions and therapeutic responses. By mimicking the microenvironment of organs such as the intestine, lung, and brain, organoids were applied in microbial pathogenesis, immune responses, and drug efficacy. Despite challenges in simulating immune dynamics and chronic infections, advancements in vascularization, immune component integration, and 3D bioprinting hold promise for breakthroughs in infectious disease research and precision medicine. This review highlights the transformative potential of organoids in understanding the mechanisms of pathogen infection and developing targeted therapies.
-
A high-throughput microfluidic platform for functional hiPSC-derived liver organoids with bile duct- and lobule-like structures.
HiPSC-derived organoids have attracted significant attention in stem cell research and regenerative medicine. However, obtaining functional organoids in sufficient quantities, consistent sizes, and reproducible formats remains a significant challenge. Here, we present an innovative microfluidic platform for the high-throughput production of HAMA core-shell microspheres (HCSM) for the encapsulation and differentiation of hiPSCs. Fish gelatin and HAMA were employed as the core and shell materials, respectively. Using this platform, we successfully fabricated HCSM with uniform and controllable sizes in a high-throughput manner. Single-cell hiPSC suspensions self-organized into spheroids within HCSM, leading to the formation of EBs exhibiting cavitation. These EBs effectively differentiated into brain organoids, beating cardiac organoids, and liver organoids. Detailed structural and functional analyses of the liver organoids revealed a heterogeneous cellular composition including hepatocyte-, bile duct epithelial-, epithelial-, and stellate-like cells. Structurally, they exhibited bile duct- and hepatic lobule-like formations. Functionally, liver organoids displayed lipid and glycogen accumulation, ICG uptake and release, albumin and urea secretion, as well as metabolic responses to APAP and rifampin. Consequently, our study introduces a high-throughput manufacturing platform for hiPSC-derived organoids, with the potential to generate functional organoids for therapeutic applications and drug screening.
-
Coaxial 3D bioprinting of self-assembled multicellular heterogeneous tumor fibers.
Three-dimensional (3D) bioprinting of living structures with cell-laden biomaterials has been achieved in vitro, however, some cell-cell interactions are limited by the existing hydrogel. To better mimic tumor microenvironment, self-assembled multicellular heterogeneous brain tumor fibers have been fabricated by a custom-made coaxial extrusion 3D bioprinting system, with high viability, proliferative activity and efficient tumor-stromal interactions. Therein, in order to further verify the sufficient interactions between tumor cells and stroma MSCs, CRE-LOXP switch gene system which contained GSCs transfected with "LOXP-STOP-LOXP-RFP" genes and MSCs transfected with "CRE recombinase" gene was used. Results showed that tumor-stroma cells interacted with each other and fused, the transcription of RFP was higher than that of 2D culture model and control group with cells mixed directly into alginate, respectively. RFP expression was observed only in the cell fibers but not in the control group under confocal microscope. In conclusion, coaxial 3D bioprinted multicellular self-assembled heterogeneous tumor tissue-like fibers provided preferable 3D models for studying tumor microenvironment in vitro, especially for tumor-stromal interactions.
-
[Recent progress in the study of gangliosides].