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Search Results (573)

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27 pages, 1370 KiB  
Review
Immune Organoids: A Review of Their Applications in Cancer and Autoimmune Disease Immunotherapy
by David B. Olawade, Emmanuel O. Oisakede, Eghosasere Egbon, Saak V. Ovsepian and Stergios Boussios
Curr. Issues Mol. Biol. 2025, 47(8), 653; https://doi.org/10.3390/cimb47080653 - 13 Aug 2025
Viewed by 814
Abstract
Immune organoids have emerged as a ground-breaking platform in immunology, offering a physiologically relevant and controllable environment to model human immune responses and evaluate immunotherapeutic strategies. Derived from stem cells or primary tissues, these three-dimensional constructs recapitulate key aspects of lymphoid tissue architecture, [...] Read more.
Immune organoids have emerged as a ground-breaking platform in immunology, offering a physiologically relevant and controllable environment to model human immune responses and evaluate immunotherapeutic strategies. Derived from stem cells or primary tissues, these three-dimensional constructs recapitulate key aspects of lymphoid tissue architecture, cellular diversity, and functional dynamics, providing a more accurate alternative to traditional two-dimensional cultures and animal models. Their ability to mimic complex immune microenvironments has positioned immune organoids at the forefront of cancer immunotherapy development, autoimmune disease modeling, and personalized medicine. This narrative review highlights the advances in immune organoid technology, with a focus on their applications in testing immunotherapies, such as checkpoint inhibitors, CAR-T cells, and cancer vaccines. It also explores how immune organoids facilitate the study of autoimmune disease pathogenesis with insights into their molecular basis and support in high-throughput drug screening. Despite their transformative potential, immune organoids face significant challenges, including the replication of systemic immune interactions, standardization of fabrication protocols, scalability limitations, biological heterogeneity, and the absence of vascularization, which restricts organoid size and maturation. Future directions emphasize the integration of immune organoids with multi-organ systems to better replicate systemic physiology, the development of advanced biomaterials that closely mimic lymphoid extracellular matrices, the incorporation of artificial intelligence (AI) to optimize organoid production and data analysis, and the rigorous clinical validation of organoid-derived findings. Continued innovation and interdisciplinary collaboration will be essential to overcome existing barriers, enabling the widespread adoption of immune organoids as indispensable tools for advancing immunotherapy, vaccine development, and precision medicine. Full article
(This article belongs to the Section Molecular Medicine)
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15 pages, 4533 KiB  
Systematic Review
State-of-the-Art Organ-on-Chip Models and Designs for Medical Applications: A Systematic Review
by Gustavo Adolfo Marcelino de Almeida Nunes, Ana Karoline Almeida da Silva, Rafael Mendes Faria, Klériston Silva Santos, Arthur da Costa Aguiar, Lindemberg Barreto Mota da Costa, Glécia Virgolino da Silva Luz, Marcella Lemos Brettas Carneiro, Mário Fabrício Fleury Rosa, Graziella Anselmo Joanitti, Karoany Maria Ibiapina, Ana Karen Gonçalves de Barros Gomes, Adson Ferreira da Rocha and Suélia de Siqueira Rodrigues Fleury Rosa
Biomimetics 2025, 10(8), 524; https://doi.org/10.3390/biomimetics10080524 - 11 Aug 2025
Viewed by 512
Abstract
Organ-on-a-chip (OoC) devices simulate human organs within a microenvironment, potentially surpassing traditional preclinical methods and paving the way for innovative treatments. A thorough understanding of the current state of OoC design enables the development of more precise and relevant models that replicate not [...] Read more.
Organ-on-a-chip (OoC) devices simulate human organs within a microenvironment, potentially surpassing traditional preclinical methods and paving the way for innovative treatments. A thorough understanding of the current state of OoC design enables the development of more precise and relevant models that replicate not only the structure of organs but also their intricate cellular interactions and responses to external stimuli. This knowledge facilitates the optimization of biomimetic materials and allows for the real-time simulation of physiological microenvironments. By keeping abreast of new microfabrication techniques, we can explore opportunities to create customized and highly functional OoCs. Objective: To provide a comprehensive overview of microphysiological platform designs. Methods: This systematic review was registered in PROSPERO under the number CRD42022352569. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The eligibility criteria included studies utilizing human tissue, either primary or secondary lineage cells. Results: A total of 9.790 papers were retrieved from the Scopus, Embase, IEEE and Web of Science databases. After removing duplicates and applying a 10-year publication filter, 3.150 articles were screened by title and abstract. Full-text analyses were then performed. Eighteen studies met the eligibility criteria and were included in this systematic review. In this review, we examine the principles of OoC design, focusing on structure, dimensions, cell culturing options and manufacturing techniques. We also examine recent advances and future prospects in the field. Conclusions: Microphysiological devices in health research can facilitate drug discovery and improve our understanding of human physiology. They contribute to more ethical research by reducing the number of animals used in experiments. Full article
(This article belongs to the Section Biomimetic Design, Constructions and Devices)
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16 pages, 3224 KiB  
Article
GelMA Core–Shell Microgel Preparation Based on a Droplet Microfluidic Device for Three-Dimensional Tumor Ball Culture and Its Drug Testing
by Xindong Yang, Yi Xu, Dongchen Zhu and Xianqiang Mi
Molecules 2025, 30(15), 3305; https://doi.org/10.3390/molecules30153305 - 7 Aug 2025
Viewed by 623
Abstract
Gelatin methacrylate (GelMA) microgels serve as promising bioscaffolds for tissue engineering and drug screening. However, conventional solid GelMA microgels often exhibit limited mass transfer efficiency and provide insufficient protection for embedded cells. In this study, we developed a droplet-based microfluidic platform to fabricate [...] Read more.
Gelatin methacrylate (GelMA) microgels serve as promising bioscaffolds for tissue engineering and drug screening. However, conventional solid GelMA microgels often exhibit limited mass transfer efficiency and provide insufficient protection for embedded cells. In this study, we developed a droplet-based microfluidic platform to fabricate core–shell structured GelMA microgels. This system enabled precise control over microgel size and core-to-shell ratio by modulating flow rates. Encapsulation of A549 cells within these core–shell microgels preserved cellular viability and facilitated the formation of three-dimensional tumor spheroids. These outcomes confirmed both the protective function of the core–shell architecture during encapsulation and the overall biocompatibility of the microgels. The developed GelMA core–shell microgel system presents considerable applicability in research domains such as organoid modeling and high-throughput pharmacological screening. Full article
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23 pages, 3665 KiB  
Communication
Drug Repurposing for Kala-Azar
by Biljana Arsić, Budimir S. Ilić, Andreas Maier, Michael Hartung, Jovana Janjić, Jelena Milićević and Jan Baumbach
Pharmaceutics 2025, 17(8), 1021; https://doi.org/10.3390/pharmaceutics17081021 - 6 Aug 2025
Viewed by 321
Abstract
Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated [...] Read more.
Objective: Visceral leishmaniasis (VL), a Neglected Tropical Disease caused by Leishmania donovani, remains insufficiently addressed by current therapies due to high toxicity, poor efficacy, and immunosuppressive complications. This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron–ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug–target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of −9.36 and −9.10 kcal/mol, and corresponding MM-GBSA ΔG_bind values of −14.00 and −13.25 kcal/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2/TYK2–STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation. Full article
(This article belongs to the Section Drug Targeting and Design)
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23 pages, 4112 KiB  
Article
Metabolic Culture Medium Enhances Maturation of Human iPSC-Derived Cardiomyocytes via Cardiac Troponin I Isoform Induction
by Daria V. Goliusova, Agnessa P. Bogomolova, Alina V. Davidenko, Kristina A. Lavrenteva, Margarita Y. Sharikova, Elena A. Zerkalenkova, Ekaterina M. Vassina, Alexandra N. Bogomazova, Maria A. Lagarkova, Ivan A. Katrukha and Olga S. Lebedeva
Int. J. Mol. Sci. 2025, 26(15), 7248; https://doi.org/10.3390/ijms26157248 - 26 Jul 2025
Viewed by 667
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (iCMs) provide a powerful platform for investigating cardiac biology. However, structural, metabolic, and electrophysiological immaturity of iCMs limits their capacity to model adult cardiomyocytes. Currently, no universally accepted criteria or protocols for effective iCMs maturation exist. This [...] Read more.
Human induced pluripotent stem cell-derived cardiomyocytes (iCMs) provide a powerful platform for investigating cardiac biology. However, structural, metabolic, and electrophysiological immaturity of iCMs limits their capacity to model adult cardiomyocytes. Currently, no universally accepted criteria or protocols for effective iCMs maturation exist. This study aimed to identify practical culture conditions that promote iCMs maturation, thereby generating more physiologically relevant in vitro cardiac models. We evaluated the effects of short- and long-term culture in media supplemented with various stimulatory compounds under 2D conditions, focusing on intracellular content and localization of slow skeletal troponin I (ssTnI) and cardiac troponin I (cTnI) isoforms. Our findings demonstrate that the multicomponent metabolic maturation medium (MM-1) effectively enhances the transition toward a more mature iCM phenotype, as evidenced by increased cTnI expression and formation of cross-striated myofibrils. iCMs cultured in MM-1 more closely resemble adult cardiomyocytes and are compatible with high-resolution single-cell techniques such as electron microscopy and patch-clamp electrophysiology. This work provides a practical and scalable approach for advancing the maturation of iPSC-derived cardiac models, with applications in disease modeling and drug screening. Full article
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33 pages, 1777 KiB  
Review
Immunomodulatory Natural Products in Cancer Organoid-Immune Co-Cultures: Bridging the Research Gap for Precision Immunotherapy
by Chang-Eui Hong and Su-Yun Lyu
Int. J. Mol. Sci. 2025, 26(15), 7247; https://doi.org/10.3390/ijms26157247 - 26 Jul 2025
Viewed by 885
Abstract
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We [...] Read more.
Natural products demonstrate potent immunomodulatory properties through checkpoint modulation, macrophage polarization, and T cell/natural killer (NK) cell activation. While cancer organoid-immune co-culture platforms enable physiologically relevant modeling of tumor–immune interactions, systematic investigation of natural product immunomodulation in these systems remains entirely unexplored. We conducted a comprehensive literature analysis examining natural products tested in cancer organoids, immunomodulatory mechanisms from traditional models, technical advances in organoid-immune co-cultures, and standardization requirements for clinical translation. Our analysis reveals a critical research gap: no published studies have investigated natural product-mediated immunomodulation using organoid-immune co-culture systems. Even though compounds like curcumin, resveratrol, and medicinal mushroom polysaccharides show extensive immunomodulatory effects in two-dimensional (2D) cultures, and organoid technology achieves high clinical correlation for drug response prediction, all existing organoid studies focus exclusively on direct cytotoxicity. Technical challenges include compound stability, limited matrix penetration requiring substantially higher concentrations than 2D cultures, and maintaining functional immune populations in three-dimensional (3D) systems. The convergence of validated organoid-immune co-culture platforms, Food and Drug Administration (FDA) regulatory support through the Modernization Act 2.0, and extensive natural product knowledge creates unprecedented opportunities. Priority research directions include systematic screening of immunomodulatory natural products in organoid-immune co-cultures, development of 3D-optimized delivery systems, and clinical validation trials. Success requires moving beyond cytotoxicity-focused studies to investigate immunomodulatory mechanisms in physiologically relevant 3D systems, potentially unlocking new precision cancer immunotherapy approaches. Full article
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14 pages, 4166 KiB  
Article
Development and Characterization of a Novel α-Synuclein-PEST H4 Cell Line for Enhanced Drug Screening in α-Synucleinopathies
by Nancy Carullo, Viktor Haellman, Simon Gutbier, Sonja Schlicht, Thien Thuong Nguyen, Rita Blum Marti, Philippe Hartz, Lothar Lindemann and Lina Schukur
Int. J. Mol. Sci. 2025, 26(15), 7205; https://doi.org/10.3390/ijms26157205 - 25 Jul 2025
Viewed by 288
Abstract
Alpha-Synuclein (α-Syn) is a presynaptic neuronal protein implicated in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, primarily through its aggregation into insoluble fibrils. The extended α-Syn half-life necessitates treatment durations that are incompatible with efficient high-throughput drug screening, can risk compound [...] Read more.
Alpha-Synuclein (α-Syn) is a presynaptic neuronal protein implicated in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, primarily through its aggregation into insoluble fibrils. The extended α-Syn half-life necessitates treatment durations that are incompatible with efficient high-throughput drug screening, can risk compound stability or cause cellular toxicity. To address this, we inserted a PEST sequence, a motif known to promote rapid protein degradation, at the C-terminus of the SNCA gene using CRISPR/Cas9 to create a novel cell line with reduced α-Syn half-life. This modification accelerates α-Syn turnover, providing a robust model for studying α-Syn dynamics and offering a platform that is applicable to other long-lived proteins. Our results demonstrate a six-fold reduction in α-Syn half-life, enabling the rapid detection of changes in protein levels and facilitating the identification of molecules that modulate α-Syn production and degradation pathways. Using inhibitors of the proteasome, transcription, and translation further validated the model’s utility in examining various mechanisms that impact protein levels. This novel cell line represents a significant advancement for studying α-Syn dynamics and offers promising avenues to develop therapeutics for α-synucleinopathies. Future research should focus on validating this model in diverse experimental settings and exploring its potential in high-throughput screening applications. Full article
(This article belongs to the Special Issue Whole-Cell System and Synthetic Biology, 2nd Edition)
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11 pages, 5546 KiB  
Proceeding Paper
RhsP2 Protein as a New Antibacterial Toxin Targeting RNA
by Tamara Nami Haj Marza
Med. Sci. Forum 2025, 35(1), 3; https://doi.org/10.3390/msf2025035003 - 24 Jul 2025
Viewed by 282
Abstract
Many bacteria, such as Pseudomonas aeruginosa, have encoded many toxins like RhsP2 that target non-coding RNAs (ncRNAs) in a similar mechanism to ART components; bacterial RNA loses its function of amino acid translation. A virtual screening approach was used to investigate RhsP2, [...] Read more.
Many bacteria, such as Pseudomonas aeruginosa, have encoded many toxins like RhsP2 that target non-coding RNAs (ncRNAs) in a similar mechanism to ART components; bacterial RNA loses its function of amino acid translation. A virtual screening approach was used to investigate RhsP2, which targets 16s rRNAs and then disrupts the translation of bacterial amino acids to proteins. Rifamycin is the bioreference as it forms a stable complex with the bacterial RNA in its active sites. Using different docking software can determine the best predicted conformations between RhsP2/16S and rRNA, and analyzing the docking score for both Affinity Binding and the root mean square deviation (RMSD) of particle coordinates helps choose the most appropriate drugs by using tools such as bioinformatics platforms and databases. Full article
(This article belongs to the Proceedings of The 4th International Electronic Conference on Antibiotics)
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20 pages, 1292 KiB  
Review
AI-Driven Polypharmacology in Small-Molecule Drug Discovery
by Mena Abdelsayed
Int. J. Mol. Sci. 2025, 26(14), 6996; https://doi.org/10.3390/ijms26146996 - 21 Jul 2025
Viewed by 813
Abstract
Polypharmacology, the rational design of small molecules that act on multiple therapeutic targets, offers a transformative approach to overcome biological redundancy, network compensation, and drug resistance. This review outlines the scientific rationale for polypharmacology, highlighting its success across oncology, neurodegeneration, metabolic disorders, and [...] Read more.
Polypharmacology, the rational design of small molecules that act on multiple therapeutic targets, offers a transformative approach to overcome biological redundancy, network compensation, and drug resistance. This review outlines the scientific rationale for polypharmacology, highlighting its success across oncology, neurodegeneration, metabolic disorders, and infectious diseases. Emphasis is placed on how polypharmacological agents can synergize therapeutic effects, reduce adverse events, and improve patient compliance compared to combination therapies. We also explore how computational methods—spanning ligand-based modeling, structure-based docking, network pharmacology, and systems biology—enable target selection and multi-target ligand prediction. Recent advances in artificial intelligence (AI), particularly deep learning, reinforcement learning, and generative models, have further accelerated the discovery and optimization of multi-target agents. These AI-driven platforms are capable of de novo design of dual and multi-target compounds, some of which have demonstrated biological efficacy in vitro. Finally, we discuss the integration of omics data, CRISPR functional screens, and pathway simulations in guiding multi-target design, as well as the challenges and limitations of current AI approaches. Looking ahead, AI-enabled polypharmacology is poised to become a cornerstone of next-generation drug discovery, with potential to deliver more effective therapies tailored to the complexity of human disease. Full article
(This article belongs to the Special Issue Techniques and Strategies in Drug Design and Discovery, 3rd Edition)
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15 pages, 2357 KiB  
Article
Development of a Novel, Highly Sensitive System for Evaluating Ebola Virus Particle Formation
by Wakako Furuyama, Miako Sakaguchi, Hanako Ariyoshi and Asuka Nanbo
Viruses 2025, 17(7), 1016; https://doi.org/10.3390/v17071016 - 19 Jul 2025
Viewed by 559
Abstract
Ebola virus (EBOV) causes severe hemorrhagic fevers in humans, and effective countermeasures remain limited. The EBOV-encoded major matrix protein VP40 is essential for viral assembly, budding, and particle release, making it a promising target for antiviral drug development. However, no approved drugs currently [...] Read more.
Ebola virus (EBOV) causes severe hemorrhagic fevers in humans, and effective countermeasures remain limited. The EBOV-encoded major matrix protein VP40 is essential for viral assembly, budding, and particle release, making it a promising target for antiviral drug development. However, no approved drugs currently target the viral particle formation process. In this study, we established a simple and highly sensitive screening system to evaluate VP40-mediated virus-like particle (VLP) formation under biosafety level −2 conditions. The system uses the HiBiT luminescence-based reporter fused to VP40, allowing for the detection of VP40 release. Our results demonstrate that the HiBiT sequence fused at the N-terminus [HiBiT-VP40 (N)] retains VP40′s ability to form VLPs, supporting its use as a functional reporter. Furthermore, we validated the system by assessing the role of Rab11-dependent trafficking in VP40-mediated budding and by evaluating the effect of nocodazole, a microtubule depolymerizer, on VLP release. This novel screening system provides a convenient and reliable platform for screening potential inhibitors targeting the late stages of EBOV infection, including viral particle formation and release. Additionally, its potential adaptability to other filoviruses suggests wide applicability in the discovery and development of additional novel therapeutic agents. Full article
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16 pages, 3493 KiB  
Article
Molecular Mechanisms of Aminoglycoside-Induced Ototoxicity in Murine Auditory Cells: Implications for Otoprotective Drug Development
by Cheng-Yu Hsieh, Jia-Ni Lin, Yi-Fan Chou, Chuan-Jen Hsu, Peir-Rong Chen, Yu-Hsuan Wen, Chen-Chi Wu and Chuan-Hung Sun
Int. J. Mol. Sci. 2025, 26(14), 6720; https://doi.org/10.3390/ijms26146720 - 13 Jul 2025
Viewed by 532
Abstract
Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology—comprising cell-model selection, transcriptomic analysis, and a gentamicin–Texas Red (GTTR) [...] Read more.
Aminoglycoside antibiotics are critical in clinical use for treating severe infections, but they can occasionally cause irreversible sensorineural hearing loss. To establish a rational pathway for otoprotectant discovery, we provide an integrated, three-tier methodology—comprising cell-model selection, transcriptomic analysis, and a gentamicin–Texas Red (GTTR) uptake assay—to guide the development of otoprotective strategies. We first utilized two murine auditory cell lines—UB/OC-2 and HEI-OC1. We focused on TMC1 and OCT2 and further explored the underlying mechanisms of ototoxicity. UB/OC-2 exhibited a higher sensitivity to gentamicin, which correlated with elevated OCT2 expression confirmed via RT-PCR and Western blot. Transcriptomic analysis revealed upregulation of PI3K-Akt, calcium, and GPCR-related stress pathways in gentamicin-treated HEI-OC1 cells. Protein-level analysis further confirmed that gentamicin suppressed phosphorylated Akt while upregulating ER stress markers (GRP78, CHOP) and apoptotic proteins (cleaved caspase 3, PARP). Co-treatment with PI3K inhibitors (LY294002, wortmannin) further suppressed Akt phosphorylation, supporting the role of PI3K-Akt signaling in auditory cells. To visualize drug entry, we used GTTR to evaluate its applicability as a fluorescence-based uptake assay in these cell lines, which were previously employed mainly in cochlear explants. Sodium thiosulfate (STS) and N-acetylcysteine (NAC) significantly decreased GTTR uptake, suggesting a protective effect against gentamicin-induced hair cell damage. In conclusion, our findings showed a complex ototoxic cascade involving OCT2- and TMC1-mediated drug uptake, calcium imbalance, ER stress, and disruption of PI3K-Akt survival signaling. We believe that UB/OC-2 cells serve as a practical in vitro model for mechanistic investigations and screening of otoprotective compounds. Additionally, GTTR may be a simple, effective method for evaluating protective interventions in auditory cell lines. Overall, this study provides molecular-level insights into aminoglycoside-induced ototoxicity and introduces a platform for protective strategies. Full article
(This article belongs to the Special Issue Hearing Loss: Molecular Biological Insights)
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20 pages, 960 KiB  
Review
Zebrafish as a Model for Translational Immuno-Oncology
by Gabriela Rodrigues Barbosa, Augusto Monteiro de Souza, Priscila Fernandes Silva, Caroline Santarosa Fávero, José Leonardo de Oliveira, Hernandes F. Carvalho, Ana Carolina Luchiari and Leonardo O. Reis
J. Pers. Med. 2025, 15(7), 304; https://doi.org/10.3390/jpm15070304 - 11 Jul 2025
Viewed by 896
Abstract
Despite remarkable progress in cancer immunotherapy, many agents that show efficacy in murine or in vitro models fail to translate clinically. Zebrafish (Danio rerio) have emerged as a powerful complementary model that addresses several limitations of traditional systems. Their optical transparency, [...] Read more.
Despite remarkable progress in cancer immunotherapy, many agents that show efficacy in murine or in vitro models fail to translate clinically. Zebrafish (Danio rerio) have emerged as a powerful complementary model that addresses several limitations of traditional systems. Their optical transparency, genetic tractability, and conserved immune and oncogenic signaling pathways enable high-resolution, real-time imaging of tumor–immune interactions in vivo. Importantly, zebrafish offer a unique opportunity to study the core mechanisms of health and sickness, complementing other models and expanding our understanding of fundamental processes in vivo. This review provides an overview of zebrafish immune system development, highlighting tools for tracking innate and adaptive responses. We discuss their application in modeling immune evasion, checkpoint molecule expression, and tumor microenvironment dynamics using transgenic and xenograft approaches. Platforms for high-throughput drug screening and personalized therapy assessment using patient-derived xenografts (“zAvatars”) are evaluated, alongside limitations, such as temperature sensitivity, immature adaptive immunity in larvae, and interspecies differences in immune responses, tumor complexity, and pharmacokinetics. Emerging frontiers include humanized zebrafish, testing of next-generation immunotherapies, such as CAR T/CAR NK and novel checkpoint inhibitors (LAG-3, TIM-3, and TIGIT). We conclude by outlining the key challenges and future opportunities for integrating zebrafish into the immuno-oncology pipeline to accelerate clinical translation. Full article
(This article belongs to the Special Issue Advances in Animal Models and Precision Medicine for Cancer Research)
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22 pages, 7820 KiB  
Article
Patient-Derived Gastric Cancer Assembloid Model Integrating Matched Tumor Organoids and Stromal Cell Subpopulations
by Irit Shapira-Netanelov, Olga Furman, Dikla Rogachevsky, Galia Luboshits, Yael Maizels, Dmitry Rodin, Igor Koman and Gabriela A. Rozic
Cancers 2025, 17(14), 2287; https://doi.org/10.3390/cancers17142287 - 9 Jul 2025
Viewed by 781
Abstract
Background/Purpose: Conventional three-dimensional in vitro tumor models often fail to fully capture the complexity of the tumor microenvironment, particularly the diverse populations of cancer-associated fibroblasts that contribute to poor prognosis and treatment resistance. The purpose of this study is to develop a [...] Read more.
Background/Purpose: Conventional three-dimensional in vitro tumor models often fail to fully capture the complexity of the tumor microenvironment, particularly the diverse populations of cancer-associated fibroblasts that contribute to poor prognosis and treatment resistance. The purpose of this study is to develop a patient-specific gastric cancer assembloid model that integrates tumor epithelial cells with matched stromal cell subtypes, each derived using tailored growth media to enhance cancer preclinical research and advance personalized therapeutic strategies. Methods: Tumor tissue was dissociated, and cells expanded in media for organoids, mesenchymal stem cells, fibroblasts, or endothelial cells. The resulting tumor-derived subpopulations were co-cultured in an optimized assembloid medium supporting each cell type’s growth. Biomarker expression was assessed by immunofluorescence staining, and transcriptomic profiles were analyzed by RNA sequencing. Drug responsiveness was evaluated using cell viability assays following treatment with various therapeutic agents. Results: The optimized co-culture conditions yielded assembloids that closely mimicked the cellular heterogeneity of primary tumors, confirmed by the expression of epithelial and stromal markers. Compared to monocultures, the assembloids showed higher expression of inflammatory cytokines, extracellular matrix remodeling factors, and tumor progression-related genes across different organoids and stromal ratios. Drug screening revealed patient- and drug-specific variability. While some drugs were effective in both organoid and assembloid models, others lost efficacy in the assembloids, highlighting the critical role of stromal components in modulating drug responses. Conclusions: This assembloid system offers a robust platform to study tumor–stroma interactions, identify resistance mechanisms, and accelerate drug discovery and personalized therapeutic strategies for gastric cancer. Full article
(This article belongs to the Section Methods and Technologies Development)
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17 pages, 1886 KiB  
Review
Random Insertion Reporter Gimmicks Powered by Cut-and-Paste DNA Transposons
by Yamato Kasahara, Kentaro Semba, Shinya Watanabe and Kosuke Ishikawa
Biomedicines 2025, 13(7), 1682; https://doi.org/10.3390/biomedicines13071682 - 9 Jul 2025
Viewed by 447
Abstract
Transposons are mobile genetic elements capable of moving within the genome. Leveraging this property—particularly the cut-and-paste mechanism of DNA transposons—has enabled the development of technologies for inserting exogenous DNA fragments into host genomes. While targeted integration is a key goal for therapeutic applications, [...] Read more.
Transposons are mobile genetic elements capable of moving within the genome. Leveraging this property—particularly the cut-and-paste mechanism of DNA transposons—has enabled the development of technologies for inserting exogenous DNA fragments into host genomes. While targeted integration is a key goal for therapeutic applications, this review highlights the value of their intrinsic randomness. By combining the ability to freely design the DNA cargo with the stochastic nature of transposon integration, it becomes possible to generate highly sensitive reporter cells. These can be used to efficiently identify functional markers, uncover novel signaling pathways, and establish innovative platforms for drug screening. As more subfamilies of transposons become available for research use, their complementary biases may enhance the coverage and diversity of genome-wide screening approaches. Although inherently unpredictable, this strategy embraces randomness as a strength, and we propose that it holds great promise for driving new advances in biology, cellular engineering, and medical research. Full article
(This article belongs to the Special Issue Gene Delivery and Gene Editing)
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23 pages, 4011 KiB  
Review
Current Advances and Future Perspectives of Liver-on-a-Chip Platforms Incorporating Dynamic Fluid Flow
by Jingyeong Yun, Tae-Joon Jeon and Sun Min Kim
Biomimetics 2025, 10(7), 443; https://doi.org/10.3390/biomimetics10070443 - 4 Jul 2025
Viewed by 725
Abstract
The liver is a vital organ responsible for a broad range of metabolic functions, including glucose and lipid metabolism, detoxification, and protein synthesis. Its structural complexity, characterized by hexagonal hepatic lobules composed of diverse parenchymal and non-parenchymal cell types, supports its broad spectrum [...] Read more.
The liver is a vital organ responsible for a broad range of metabolic functions, including glucose and lipid metabolism, detoxification, and protein synthesis. Its structural complexity, characterized by hexagonal hepatic lobules composed of diverse parenchymal and non-parenchymal cell types, supports its broad spectrum of physiological activities. Traditional in vitro liver models have contributed significantly to our understanding of hepatic biology and the development of therapies for liver-related diseases. However, static culture systems fail to replicate the dynamic in vivo microenvironment, particularly the continuous blood flow and shear stress that are critical for maintaining hepatocyte function and metabolic zonation. Recent advances in microphysiological systems (MPS) incorporating dynamic fluid flow have addressed these limitations by providing more physiologically relevant platforms for modeling liver function. These systems offer improved fidelity for applications in drug screening, toxicity testing, and disease modeling. Furthermore, the integration of liver MPS with other organ models in multi-organ-on-chip platforms has enabled the investigation of inter-organ crosstalk, enhancing the translational potential of in vitro systems. This review summarizes recent progress in the development of dynamic liver MPS, highlights their biomedical applications, and discusses future directions for creating more comprehensive and predictive in vitro models. Full article
(This article belongs to the Special Issue Organ-on-a-Chip Platforms for Drug Delivery and Tissue Engineering)
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