Cells

16 pages, 4273 KB

Open AccessArticle

Texture Analysis of Histology Images for Characterizing Ultrasound-Stimulated Microbubble Radiation Enhancement Treatment Response

by Lakshmanan Sannachi, Serena Mohabir, Evan McNabb, Deepa Sharma, Anoja Giles, Wenyi Yang, Kai Xuan Leong, Martin Stanisz and Gregory J. Czarnota

Cells 2025, 14(24), 2023; https://doi.org/10.3390/cells14242023 - 18 Dec 2025

Cited by 1 | Viewed by 661

Abstract

Ultrasound-stimulated microbubble (USMB) therapy, in combination with radiotherapy (XRT), represents a promising approach to enhancing the efficacy of conventional cancer treatments by targeting tumor vasculature. Recent preclinical studies using MRI-guided focused ultrasound have demonstrated that USMB enhances radiation effects in tumor blood vessels, [...] Read more.

Ultrasound-stimulated microbubble (USMB) therapy, in combination with radiotherapy (XRT), represents a promising approach to enhancing the efficacy of conventional cancer treatments by targeting tumor vasculature. Recent preclinical studies using MRI-guided focused ultrasound have demonstrated that USMB enhances radiation effects in tumor blood vessels, resulting in significantly greater tumor cell death than radiation alone. Dynamic contrast-enhanced MRI (DCE-MRI) has been instrumental in this methodology in mapping tumor perfusion heterogeneity, allowing for precise targeting of additional USMB and XRT to specific vascular regions. This study employed four advanced texture analysis methods, GLCM, GLDM, GLSZM, and NGTDM, to quantitatively assess changes in the cellular structure of prostate tumors following different treatments, including combinations of USMB and XRT targeted to low- and high-perfusion regions. Texture features, particularly those derived from GLCM, GLDM, and GLSZM, revealed significant differences in cell structure patterns across treatment groups. The GLSZM methodology was identified as the most sensitive method for detecting treatment-induced structural changes, effectively identifying regions of necrosis and varied stages of cell death. Texture-derivative analyses further highlighted intra-tumoral heterogeneity, especially in response to additional USMB + XRT treatments. These results align with findings in other tissue models, underscoring the value of texture analysis for monitoring treatment response. Full article

(This article belongs to the Section Cellular Pathology)

► Show Figures

Figure 1

22 pages, 4207 KB

Open AccessArticle

SS18::SSX and BRD9 Modulate Synovial Sarcoma Differentiation

by Anna Kuntze, Victor Banerjee, Marcel Trautmann, Charlotte Pünt, Ruth Berthold, Pascal Hauser, Lucas Scholl, Eva Wardelmann, Kornelius Kerl, Wolfgang Hartmann and Ilka Isfort

Cells 2025, 14(24), 2022; https://doi.org/10.3390/cells14242022 - 18 Dec 2025

Viewed by 804

Abstract

Synovial sarcoma (SySa) is a malignant soft tissue tumor that is characterized by an SS18::SSX fusion protein, which integrates into BAF chromatin remodeling complexes and alters global gene transcription. Despite its uniform genetic driver, SySa displays striking histomorphological and phenotypic heterogeneity, including spindle [...] Read more.

Synovial sarcoma (SySa) is a malignant soft tissue tumor that is characterized by an SS18::SSX fusion protein, which integrates into BAF chromatin remodeling complexes and alters global gene transcription. Despite its uniform genetic driver, SySa displays striking histomorphological and phenotypic heterogeneity, including spindle cell, glandular and poorly differentiated patterns. Prognosis is variable, with around 50% of patients developing metastases. Limited response to chemotherapy highlights the need for a better understanding of the underlying molecular mechanisms to guide alternative therapeutic strategies. Given the pivotal function of BAF complexes in SySa and their recently described impact on cellular differentiation processes, this study aims to investigate the role of SS18::SSX and specific BAF subunits in SySa differentiation. Nanostring analysis revealed that silencing of SS18::SSX and the GBAF subunit BRD9 modulates the cellular differentiation pathways. SS18::SSX and BRD9 were found to regulate epithelial–mesenchymal-transition (EMT)-associated factors of Snail and Slug on different levels, with SS18::SSX repressing E-Cadherin expression. Published single-cell RNA sequencing data were analyzed to validate our finding that BRD9 contributes to SySa EMT regulation. Our study provides novel insights into the multilayered regulation of key EMT players by SS18::SSX and BRD9 in SySa, thereby defining tumor phenotype and (potentially) prognosis. Full article

► Show Figures

Figure 1

44 pages, 3017 KB

Open AccessReview

Peroxisomes, PPARs, and Their Role in Macrophages

by Anggi Muhtar Pratama, Heike Bömmel, Hevi Wihadmadyatami, Yudy Tjahjono, Süleyman Ergün, Akash Bachhuka and Srikanth Karnati

Cells 2025, 14(24), 2021; https://doi.org/10.3390/cells14242021 - 18 Dec 2025

Viewed by 1105

Abstract

Macrophages are versatile immune cells capable of modifying their functions based on their location and the specific requirements of the immune response. They polarize into the M1 phenotype when stimulated by inflammatory agents. In contrast to resolve inflammation and to facilitate tissue repair, [...] Read more.

Macrophages are versatile immune cells capable of modifying their functions based on their location and the specific requirements of the immune response. They polarize into the M1 phenotype when stimulated by inflammatory agents. In contrast to resolve inflammation and to facilitate tissue repair, macrophages polarize into the M2 phenotype. Polarization alters the cellular composition of the macrophages, including peroxisomes and peroxisome proliferator-activated receptors (PPARs). In macrophages, peroxisomes and PPARs perform at least three key roles: mediating inflammation, reducing oxidative stress, and regulating lipid metabolism. We review the functional role of peroxisomes and PPARs on macrophage biology focusing on adaptive mechanisms during these processes. The insights gained from this analysis are expected to lead to new advancements in treating inflammation and immune-related disorders, including autoimmune disorders, metabolic inflammation, and neurodegenerative conditions. Full article

► Show Figures

Graphical abstract

18 pages, 10030 KB

Open AccessArticle

Ameliorative Effects of Vitamin E and Lutein on Hydrogen Peroxide-Triggered Oxidative Cytotoxicity via Combined Transcriptome and Metabolome Analysis

by Hongrui Lv, Yongji He and Shang Guo

Cells 2025, 14(24), 2020; https://doi.org/10.3390/cells14242020 - 18 Dec 2025

Viewed by 657

Abstract

Vitamin E and lutein both belong to food functional factors, which have cytoprotective potential and antioxidant effects. However, mechanism details at cell level remain scarce. In this study, HepG2 cells were utilized to inquire and compare the ameliorative effects of vitamin E and [...] Read more.

Vitamin E and lutein both belong to food functional factors, which have cytoprotective potential and antioxidant effects. However, mechanism details at cell level remain scarce. In this study, HepG2 cells were utilized to inquire and compare the ameliorative effects of vitamin E and lutein under H₂O₂-induced oxidative stress through a combined transcriptomic and metabolomic profiling, in addition to physiology and biochemistry determination. Cell cytotoxicity caused by H₂O₂ was ameliorated by vitamin E or lutein as evidenced by elevating cell viability and balancing the redox system. Vitamin E had greater efficacy on ameliorating oxidative cytotoxicity than lutein. Transcriptome data revealed that differentially expressed genes were mainly enriched in the transport-related, enzyme-related, and oxidative stress-related GO terms with vitamin E pretreatment. Extracellular organization-related, biological process-related, and apoptosis-related GO terms were meaningfully enriched with lutein pretreatment. Metabolome data showed that with vitamin E ameliorative effects, the disturbed metabolic pathways included thiamine metabolism, vitamin digestion and absorption, and ABC transporters. With lutein ameliorative effects, KEGG pathway analysis showed enrichment of amino sugar and nucleotide sugar metabolism, pyrimidine metabolism, and starch and sucrose metabolism. Collectively, our study provides essential insights into utilization of vitamin E and lutein as a potential supplement for effective therapy of disease associated with oxidative stress. Full article

► Show Figures

Figure 1

17 pages, 18270 KB

Open AccessArticle

Golgi-Associated Protein JAKMIP2 Is Linked to the Centrosome and Performs Microtubule-Related Functions

by Evgeniia Ulas, Ilya Brodsky, Petros Padaryan and Anton Burakov

Cells 2025, 14(24), 2019; https://doi.org/10.3390/cells14242019 - 18 Dec 2025

Viewed by 667

Abstract

Microtubules are present in all eukaryotes, and their spatial organization in the cells depends on the function of microtubule-organizing centers (MTOCs). Various organelles may act in this capacity, including the centrosome, Golgi, nuclear envelope, endosomes, and others. The molecular mechanisms that facilitate microtubule [...] Read more.

Microtubules are present in all eukaryotes, and their spatial organization in the cells depends on the function of microtubule-organizing centers (MTOCs). Various organelles may act in this capacity, including the centrosome, Golgi, nuclear envelope, endosomes, and others. The molecular mechanisms that facilitate microtubule nucleation and/or anchoring at MTOCs are diverse. Many proteins can participate in these processes while localized to different MTOCs—either simultaneously on several or alternately on each of them. Here we studied the Golgi-associated protein JAKMIP2 in various cells using the methods of fluorescent multichannel confocal microscopy with subsequent image analysis via our own algorithm, transfection with a genetic construct encoding a fused protein of interest, and microtubule recovery monitoring during nocodazole washout. We demonstrated for the first time that JAKMIP2 is present on centrosomes in various cells. We also found that its abundance at this location is dependent on the cell cycle stage. Furthermore, we showed that an excess of JAKMIP2 specifically impairs centrosome function as a MTOC. Finally, our data indicates that exogenous JAKMIP2 slows down centrosomal microtubule nucleation and may also affect their anchoring. Our findings make a new contribution to the existing knowledge of the molecular mechanisms of the centrosome’s function as a MTOC. Full article

(This article belongs to the Special Issue Mechanisms Underlying Cell Growth and Development)

► Show Figures

Figure 1

21 pages, 5654 KB

Open AccessArticle

Neutrophil Extracellular Traps Promote Platelet-Driven Contraction of Inflammatory Blood Clots via Local Generation of Endogenous Thrombin and Softening of the Fibrin Network

by Shakhnoza M. Saliakhutdinova, Rafael R. Khismatullin, Alina I. Khabirova, Rustem I. Litvinov and John W. Weisel

Cells 2025, 14(24), 2018; https://doi.org/10.3390/cells14242018 - 18 Dec 2025

Viewed by 999

Abstract

Immunothrombosis can substantially affect the course and outcomes of severe infections and immune-mediated diseases. While inflammatory thrombi are neutrophil-rich, impact of neutrophils on clot contraction, a key modulator of thrombus stability and obstructiveness, was unknown. This study investigated how neutrophils and neutrophil extracellular [...] Read more.

Immunothrombosis can substantially affect the course and outcomes of severe infections and immune-mediated diseases. While inflammatory thrombi are neutrophil-rich, impact of neutrophils on clot contraction, a key modulator of thrombus stability and obstructiveness, was unknown. This study investigated how neutrophils and neutrophil extracellular traps (NETs) affect the rate and extent of platelet-driven clot contraction. Isolated human neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) to induce NETosis, confirmed by fluorescence microscopy and scanning electron microscopy. Thrombin-induced clots, formed from whole blood or platelet-rich plasma, were supplemented with non-activated or PMA-activated neutrophils. Clot contraction kinetics and viscoelasticity were analyzed. PMA-activated neutrophils significantly enhanced the rate and final extent of clot contraction compared to controls. This promoting effect was abolished by deoxyribonuclease (DNAse) I, confirming that it was mediated by NETs embedded in the fibrin network. The factor Xa inhibitor rivaroxaban also abrogated this effect, indicating a role for NET-induced endogenous thrombin generation and platelet hyperactivation. Thromboelastography revealed that NETs made clots softer and more deformable. We conclude that activated neutrophils promote clot contraction via NETs embedded in the fibrin network, which enhance platelet contractility via endogenous thrombin production and increase clot deformability, suggesting that inflammatory thrombosis may require treatments addressing this enhanced contractility. Full article

(This article belongs to the Special Issue Molecular and Cellular Insights into Platelet Function, 2nd Edition)

► Show Figures

Graphical abstract

19 pages, 7200 KB

Open AccessArticle

Cardiomyocyte Glucocorticoid Receptors Exacerbate Stress Effects in Myocardial Ischemia Injury in Mice

by Analilia Cardenas-Garza, Lilly A. Kamberov, Hemangini A. Dhaibar, Tanja Dudenbostel, Gopi Krishna Kolluru, Christopher G. Kevil, Robert H. Oakley, John A. Cidlowski, Luca Cucullo and Diana Cruz-Topete

Cells 2025, 14(24), 2017; https://doi.org/10.3390/cells14242017 - 18 Dec 2025

Viewed by 1335

Abstract

An increase in mental stress is a recognized risk factor for cardiovascular disease (CVD). The present study investigated the relationships between stress, glucocorticoid receptors (GR), and ischemia/reperfusion (I/R) injury. We subjected male and female mice lacking cardiomyocyte GR (CardioGRKO) and their respective controls [...] Read more.

An increase in mental stress is a recognized risk factor for cardiovascular disease (CVD). The present study investigated the relationships between stress, glucocorticoid receptors (GR), and ischemia/reperfusion (I/R) injury. We subjected male and female mice lacking cardiomyocyte GR (CardioGRKO) and their respective controls to a murine model of mental stress (restraint stress). Following stress exposure, mice from both experimental and control groups underwent I/R injury via surgical ligation of the left anterior descending coronary artery. Our findings suggest that the absence of cardiomyocyte GR mitigates the detrimental effects of restraint stress on infarct size and improves post-I/R survival rates in female mice. We found that cardiomyocyte GR deficiency protects the female heart from stress-induced damage by reducing oxidative stress (superoxide and lipid peroxide production). This study is the first to test the impact of systemic stress on cardiomyocyte GR activation, linking it to redox stress in the heart during I/R injury. Our findings provide proof of concept that stress exacerbates cardiomyocyte GR-mediated responses to myocardial infarction (MI) in the female heart. These insights may contribute to the development of sex-specific treatments and therapies tailored for women. Full article

(This article belongs to the Special Issue Sex Differences in Cardiovascular Structure and Function—from Mechanisms to Therapeutics)

► Show Figures

Graphical abstract

32 pages, 22803 KB

Open AccessArticle

Highly Efficient Site-Specific and Cassette Mutagenesis of Plasmids Harboring GC-Rich Sequences

by Paulina Varela-Castillo, Ethan Zhou, Arezousadat Razavi, Elham Ebrahimi and Xiang-Jiao Yang

Cells 2025, 14(24), 2016; https://doi.org/10.3390/cells14242016 - 18 Dec 2025

Cited by 2 | Viewed by 970

Abstract

GC-rich sequences affect DNA replication, recombination and repair, as well as RNA transcription in vivo. Such sequences may also impede site-directed mutagenesis in vitro. P3a site-directed mutagenesis is a highly efficient method, but it has not been tested with plasmids possessing GC-rich sequences. [...] Read more.

GC-rich sequences affect DNA replication, recombination and repair, as well as RNA transcription in vivo. Such sequences may also impede site-directed mutagenesis in vitro. P3a site-directed mutagenesis is a highly efficient method, but it has not been tested with plasmids possessing GC-rich sequences. Here we report that it is very efficient with a BRPF3 expression vector but unsuccessful with that for KAT2B. Because two GC-rich regions located within the synthetic CAG promoter and the KAT2B coding region may form guanine (G)-quadruplexes and hinder plasmid denaturation during PCR, we developed P3b site-specific mutagenesis, achieving an average efficiency of 97.5% in engineering ten KAT2B mutants. Importantly, deletion mutagenesis revealed that either of the two GC-rich regions is sufficient for rendering the plasmid incompatible with P3a mutagenesis. Consistent with this, only P3b mutagenesis worked efficiently with several widely used sgRNA/Cas9 expression vectors, which contain the CAG promoter, and with an expression vector for CDK13, which possesses an intrinsically disordered domain encoded by a GC-rich DNA fragment. Thus, this study highlights serious challenges posed by GC-rich sequences to site-directed mutagenesis and provides an effective remedy to address such challenges. The findings support that G-quadruplex formation is one mechanism whereby such sequences impede regular PCR-based mutagenesis methods. Full article

(This article belongs to the Section Cell Methods)

► Show Figures

Graphical abstract

18 pages, 1285 KB

Open AccessArticle

Chronic Treatment with Curcumin Prevents Vascular Dysfunction in the Aorta of Type 1 Diabetes by Restoring Ca²⁺ Mishandling and Modulating HSP70 Levels

by Swasti Rastogi, Anna Grimm, Brooke Biby, Lucila Mathieu, Brian Trinh and Kenia Pedrosa Nunes

Cells 2025, 14(24), 2015; https://doi.org/10.3390/cells14242015 - 17 Dec 2025

Cited by 1 | Viewed by 833

Abstract

Vascular Smooth Muscle Cells (VSMC) dysfunction is a major contributor to Type 1 diabetes (T1D)-associated vascular complications. Ca²⁺ is a key messenger responsible for maintaining VSMC tone and function, and alterations in its cytosolic levels are central to diabetes-related vasculopathy. Heat Shock [...] Read more.

Vascular Smooth Muscle Cells (VSMC) dysfunction is a major contributor to Type 1 diabetes (T1D)-associated vascular complications. Ca²⁺ is a key messenger responsible for maintaining VSMC tone and function, and alterations in its cytosolic levels are central to diabetes-related vasculopathy. Heat Shock Protein 70 (HSP70), a multifaceted chaperone present intracellularly (iHSP70), regulates vascular reactivity by supporting Ca²⁺ handling, and extracellularly (eHSP70) activates immune signaling. Disruption of eHSP70/iHSP70 balance has been implicated in T1D-associated VSMC dysfunction. Curcumin, a phytochemical found in turmeric, is an emerging therapeutic adjuvant for treating a wide range of pathologies, including diabetes. However, whether curcumin modulates Ca²⁺ dynamics and HSP70 expression, thereby improving VSMC function, in diabetic aorta remains unclear. To investigate this, Streptozotocin-induced diabetic rats (i.p. 65 mg/kg) were treated with curcumin (300 mg/kg) for 28 days. Vascular function was evaluated using wire myography to assess changes in biphasic contraction curve and Ca²⁺ dynamics, while HSP70 was quantified using Western blotting and ELISA. Structural alterations were analyzed by assessing collagen and elastin using Picrosirius staining and fluorescence microscopy. Chronic curcumin treatment improved vascular function by normalizing Ca²⁺ mishandling, restoring the eHSP70/iHSP70 ratio, reducing hypercontractility, and mitigating arterial structural alterations. These findings indicate that curcumin could potentially ameliorate diabetes-related VSMC dysfunction by restoring Ca²⁺ homeostasis and modulating HSP70. Full article

► Show Figures

Figure 1

45 pages, 3742 KB

Open AccessReview

Metabolic Stress and Adaptation in Pancreatic β-Cells to Hypoxia: Mechanisms, Modulators, and Implications for Transplantation

by Jannat Akram, Prianna Menezes, Noorul Ibtesam Idris, Joanna Eliza Thomas, Radwan Darwish, Afrin Tania, Alexandra E. Butler and Abu Saleh Md Moin

Cells 2025, 14(24), 2014; https://doi.org/10.3390/cells14242014 - 17 Dec 2025

Cited by 1 | Viewed by 1642

Abstract

Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic [...] Read more.

Pancreatic β-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs β-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1α and HIF-2α) orchestrate transcriptional programs that shift β-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive β-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin–NFAT or oxygen-binding globins—offer potential to preserve β-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell–derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on β-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of β-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation. Full article

(This article belongs to the Section Cellular Metabolism)

► Show Figures

Figure 1

30 pages, 482 KB

Open AccessReview

Hepatoblastoma Cell Lines: Past, Present and Future

by Edward V. Prochownik, Colin M. Henchy and Huabo Wang

Cells 2025, 14(24), 2013; https://doi.org/10.3390/cells14242013 - 17 Dec 2025

Cited by 1 | Viewed by 908

Abstract

Hepatoblastoma (HB), the most common pediatric liver malignancy, tends to be highly curable although advanced or recurrent disease has less favorable outcomes. Because patients are invariably <3–4 years of age, chemotherapies can cause significant long-term morbidities. Immortalized HB cell lines could be of [...] Read more.

Hepatoblastoma (HB), the most common pediatric liver malignancy, tends to be highly curable although advanced or recurrent disease has less favorable outcomes. Because patients are invariably <3–4 years of age, chemotherapies can cause significant long-term morbidities. Immortalized HB cell lines could be of great utility for drug screening, for the identification of novel therapeutic susceptibilities, and for studies requiring highly regulated and/or rapidly changing in vitro environments. However, HB research is hampered by a paucity of these lines that could be used for such purposes, with only two human cell lines being readily available, neither of which represents the most common HB molecular subtypes. Recently, immortalized cell lines have been derived from murine HBs that are driven by the most common oncogenes and tumor suppressors associated with human tumors. These comprise five distinct groups associated with the deregulation of each of the four possible combinations of oncogenic forms of the β-catenin, YAP and NRF2 transcription factors or the over-expression of MYC. All five groups share many of the attributes and molecular signatures of actual human HBs. In addition, they have been used for purposes as diverse as identifying novel molecular targets through the use of Crispr-based screens and the demonstration that some HB cells can trans-differentiate into endothelial cells that facilitate tumor growth. The experience gained from these models and advances in the propagation of human hepatocytes in mice suggests that it may soon be possible to generate bespoke human immortalized human cell lines. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors: Molecular Mechanisms and Therapeutic Strategies)

15 pages, 13819 KB

Open AccessArticle

Preclinical Evaluation of the Assembly Modulator PAV-615 in a Mouse Model of C9orf72-Associated ALS/FTD

by Jingfen Su, Jorge Alaiz Noya, Anuradha F. Lingappa, Dennis Solas, Jimei Tong, Lillian Daughrity, Monica Castanedes-Casey, Aishe Kurti, Dennis W. Dickson, Vishwanath R. Lingappa, Leonard Petrucelli and Yongjie Zhang

Cells 2025, 14(24), 2012; https://doi.org/10.3390/cells14242012 - 17 Dec 2025

Viewed by 901

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G₄C₂ repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most [...] Read more.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases that share clinical and pathological features, as well as genetic causes. A G₄C₂ repeat expansion in chromosome 9 open reading frame 72 (C9orf72) is the most common genetic cause of ALS and FTD, collectively referred to as c9ALS/FTD. Assembly modulation is a new therapeutic approach which appears to target allosteric sites on aberrant forms of multi-protein complexes and restore them to the healthy state. Recent findings demonstrate that tetrahydroisoquinolone (THIQ)-based protein assembly modulators can ameliorate ALS/FTD-associated phenotypes in cellular and animal models. In the present study, we investigated the effects of PAV-615, a novel and advanced THIQ-based modulator, in a c9ALS/FTD mouse model expressing 149 G₄C₂ repeat expansions (referred to as 149R mouse model). Specifically, PAV-615 was administered to 5-month-old 149R mice via intraperitoneal injection for one month. Motor function was evaluated using the hang wire test, while anxiety-like behavior and hyperactivity were assessed using the open-field test. Pathological markers, including dipeptide repeat (DPR) proteins, phosphorylated TAR DNA-binding protein 43 (pTDP-43) and ataxin 2-positive stress granules, were quantified by Meso Scale Discovery and immunohistochemistry assays. Compared with vehicle-treated controls, PAV-615 significantly improved motor performance and modestly reduced anxiety-like behavior and hyperactivity in 149R mice. Moreover, PAV-615 treatment significantly decreased cortical DPR, pTDP-43 and ataxin 2-positive stress granule burdens. These results support assembly modulation as a promising therapeutic approach treatment of ALS/FTD. Full article

(This article belongs to the Special Issue Novel and Experimental Strategies for the Treatment of Neurodegenerative Diseases)

► Show Figures

Figure 1

24 pages, 4525 KB

Open AccessArticle

Dietary Interventions Modulate Cell Competition and Locomotor Decline in an Alzheimer’s Disease Drosophila Model

by Carolina Costa-Rodrigues, Jovin R. Jacobs, Joana Couceiro, Catarina Brás-Pereira and Eduardo Moreno

Cells 2025, 14(24), 2011; https://doi.org/10.3390/cells14242011 - 17 Dec 2025

Cited by 1 | Viewed by 831

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterised by Amyloid-beta 42 (Aβ42) plaque accumulation and cognitive decline, with current treatments focused on symptomatic relief. Emerging therapeutics, such as dietary interventions, can modulate cognitive decline and delay AD progression. Our previous work in Drosophila [...] Read more.

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterised by Amyloid-beta 42 (Aβ42) plaque accumulation and cognitive decline, with current treatments focused on symptomatic relief. Emerging therapeutics, such as dietary interventions, can modulate cognitive decline and delay AD progression. Our previous work in Drosophila melanogaster identified cell competition as a key mechanism that eliminates unfit neurons in an AD model, improving locomotion by removing the unfit neurons expressing flower^LoseB and ahuizotl (azot). Here, we explored how diet influences azot-dependent cell competition and locomotion in the AD model. Flies were fed with either a yeast-based diet (YBD) or a synthetic (SAA) diet for up to 28 days. In contrast to YBD, SAA delayed cell competition activation until day 21, coinciding with locomotion improvement and delayed Aβ formation. The overexpression of the human Flower (hFWE) isoforms in a Drosophila neuronal context revealed functional conservation: hFWE1 acted as the sole loser isoform, and hFWE2 as a winner isoform. With the YBD, forcing cell competition by expressing hFWE2 in the AD model led to an accumulation of unfit cells and promoted worse locomotion phenotypes over time compared to with the SAA diet. Our data highlights the complex interaction between diet, cell competition, and Aβ toxicity, offering new therapeutic insights. Full article

► Show Figures

Graphical abstract

17 pages, 1631 KB

Open AccessArticle

Functionally Distinct Shed Subpopulations Detected After Magnetic-Activated Cell Sorting of CD71 and CD146

by Marina Miteva, Emilia Karova, Natalia Grancharova, Mirela Marinova-Takorova, Violeta Dogandzhiyska, Krasimir Hristov, Nikolay Ishkitiev, Vanyo Mitev, Evgeniy Aleksiev and Zornitsa Mihaylova

Cells 2025, 14(24), 2010; https://doi.org/10.3390/cells14242010 - 17 Dec 2025

Cited by 1 | Viewed by 554

Abstract

Mesenchymal stem cells derived from human exfoliated deciduous teeth (SHED) are a promising source for regenerative therapies due to their multipotency, proliferative capacity, and immunomodulatory properties. The present study aimed to isolate and characterize SHED subpopulations based on CD71 and CD146 expression and [...] Read more.

Mesenchymal stem cells derived from human exfoliated deciduous teeth (SHED) are a promising source for regenerative therapies due to their multipotency, proliferative capacity, and immunomodulatory properties. The present study aimed to isolate and characterize SHED subpopulations based on CD71 and CD146 expression and evaluate their multilineage differentiation potential. SHED were obtained from pediatric donors and separated into CD71⁺, CD71⁻, CD146⁺, and CD146⁻ fractions using magnetic-activated cell sorting (MACS). CD71⁺/CD71⁻ and CD146⁺/CD146⁻ populations were isolated independently; no simultaneous double sorting for both markers was performed. Immunocytochemistry was employed to confirm the expression of surface and intracellular markers, including STRO-1, CD44, nestin, and vimentin. Multilineage differentiation assays toward osteogenic, adipogenic, and chondrogenic lineages revealed that CD71⁺ cells exhibited reduced osteogenic capacity compared to CD71⁻ cells, whereas CD146⁺ cells showed enhanced osteogenic and adipogenic differentiation. Chondrogenic differentiation seemed unaffected by marker expression under the 2D conditions employed. These results highlight functional heterogeneity within SHED populations and indicate that CD71 and CD146 independently influence differentiation outcomes. The selective enrichment of CD146⁺ SHED may enhance osteogenic and adipogenic regenerative applications, while CD71⁺ subsets may serve as a valuable model for studying proliferation and paracrine effects. Limitations include the use of in vitro differentiation assays and the absence of in vivo validation; additionally, combined CD71/CD146 analysis may further clarify the relationship between metabolic activity and stem/progenitor niche characteristics. Overall, marker-based characterization of SHED subpopulations provides insight into their biological properties and potential utility in targeted cell-based therapeutic strategies. Full article

(This article belongs to the Special Issue Modulation of Senescence and Differentiation in Human Mesenchymal Stem Cells)

► Show Figures

Figure 1

16 pages, 1256 KB

Open AccessArticle

Liraglutide-Driven Weight Loss Modulates Placental Remodeling in Obese Pregnancies in Mice

by Natassia Rodrigo, Dunja Aksentijevic, Nikayla Patel, Carol A. Pollock, Lana McClements and Sarah J. Glastras

Cells 2025, 14(24), 2009; https://doi.org/10.3390/cells14242009 - 17 Dec 2025

Cited by 1 | Viewed by 734

Abstract

Background: The placenta stands at the maternal–fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu [...] Read more.

Background: The placenta stands at the maternal–fetal interface and is a key organ regulating the intrauterine environment. In pregnancies exposed to obesity, placental function, signaling, and nutrient handling are adversely altered. Pre-conception weight loss is a potential intervention to alter an obesogenic milieu of pregnancy, which we investigated in a mouse model of maternal obesity using diet or administration of the glucagon-like peptide-1 (GLP-1) receptor agonist liraglutide. Methods: Pre-pregnancy weight loss in C57BL/6 high-fat diet (HFD)-fed dams was induced in the pre-pregnancy period by switching diet from HFD to chow diet or administering liraglutide (0.3 mg/kg/day subcutaneously for 4 weeks) whilst continuing HFD. In addition, a group of HFD-fed dams were switched to chow diet post-conception. The metabolomic profile and gene expression within the placenta was compared at day 18–20 of gestation. Results: ¹H NMR spectroscopy metabolomic analysis of placenta of HFD mice showed an altered amino acid metabolomic profile, with lower aspartate, glutamate, and glutamine levels compared to the placenta of chow-fed mice (p < 0.05). Meanwhile, gene expression analysis identified both oxidative stress and inflammation in the placentas of HFD-fed dams. Whilst dietary modification alone was sufficient to reduce markers of oxidative stress and inflammation, liraglutide treatment modulated pathological changes, including placental metabolic stress but not inflammation. Conclusions: These findings highlight the importance of dietary or pharmacological interventions in the pre- or immediate post-conception period, with pre-conception offering a critical window to reduce aberrant placental changes induced by obesity. Full article

(This article belongs to the Special Issue Cellular Mechanisms in Pregnancy and Foetal Development)

► Show Figures

Figure 1

19 pages, 8155 KB

Open AccessArticle

Hybrid Adjuvant-Allergen H1sD2 Proteoforms Enhance Innate Immunity Activation via Distinct N-Glycosylation Profiles

by Zorana Lopandić, Maša Babović, Tina Ravnsborg, Marina Atanasković-Marković, Ole N. Jensen and Marija Gavrović-Jankulović

Cells 2025, 14(24), 2008; https://doi.org/10.3390/cells14242008 - 16 Dec 2025

Viewed by 1434

Abstract

Novel adjuvants are key to making allergen-specific immunotherapy (AIT) safer and more effective. Their development is crucial for moving AIT into a new generation of precision medicine. N-glycosylation of protein antigens plays a pivotal role in modulating innate immune responses through enhanced recognition [...] Read more.

Novel adjuvants are key to making allergen-specific immunotherapy (AIT) safer and more effective. Their development is crucial for moving AIT into a new generation of precision medicine. N-glycosylation of protein antigens plays a pivotal role in modulating innate immune responses through enhanced recognition by pattern recognition receptors. New AIT vaccine strategies aim to exploit this by using innate-targeting adjuvants, modifying allergen structures, and routing early responses toward tolerance. Thus, we engineered five distinct N-glycosylated adjuvant configurations, composed of the receptor-binding domain of hemagglutinin (H1s) and Der p 2 (D2) allergen, to explore how glycan profile affects innate immune response for the application in therapeutic strategies for Type 1 hypersensitivity. Glycoengineered proteoforms produced in Pichia pastoris were structurally verified by mass spectrometry. Using M0 and M2 THP-1-derived macrophages, binding of all H1sD2 proteoforms to DC-SIGN was confirmed via confocal microscopy and flow cytometry. Stimulation of PBMCs with these proteoforms led to increased IL-10 and IFN-γ levels, indicating a shift toward regulatory immune responses. Notably, the M2 glycovariant elicited the strongest immunomodulatory signature, suggesting significant promise as a therapeutic candidate. These findings support the potential of glycoengineered allergen-adjuvant proteoforms to fine-tune innate immunity and improve the safety and efficacy of AIT. Full article

(This article belongs to the Section Cellular Immunology)

► Show Figures

Figure 1

18 pages, 2570 KB

Open AccessArticle

Metabolic Astrocytic Support with Decanoic Acid Enhances Energy Metabolism in Alzheimer’s Disease Models

by Aishat O. Ameen, Maja B. Rindshøj, Katarina Stoklund Dittlau, Karin Borges, Kristine K. Freude and Blanca I. Aldana

Cells 2025, 14(24), 2007; https://doi.org/10.3390/cells14242007 - 16 Dec 2025

Viewed by 722

Abstract

Alzheimer’s disease (AD) is increasingly recognized as a disorder of cerebral energy metabolism, where impaired glucose utilization contributes to disease pathology. Medium-chain fatty acids (MCFAs), such as decanoic acid (C10), have emerged as promising metabolic substrates due to their ability to bypass glycolytic [...] Read more.

Alzheimer’s disease (AD) is increasingly recognized as a disorder of cerebral energy metabolism, where impaired glucose utilization contributes to disease pathology. Medium-chain fatty acids (MCFAs), such as decanoic acid (C10), have emerged as promising metabolic substrates due to their ability to bypass glycolytic deficits and support mitochondrial function. In this study, we investigated the metabolic impact of C10 in the 5xFAD mouse model of AD and in human induced pluripotent stem cell (hiPSC)-derived astrocytes carrying familial AD mutations. Utilizing stable ¹³C-labeled metabolic tracers, we demonstrated that while [U-¹³C]glucose metabolism was largely preserved in cortical slices of 6-month-old 5xFAD female mice, [1,2-¹³C]acetate uptake was significantly reduced, suggesting impaired astrocytic metabolism. [U-¹³C]C10 was efficiently metabolized in both WT and 5xFAD brain slices, particularly in astrocytes, as indicated by high labeling of glutamine and citrate. Furthermore, C10 competitively inhibited glucose and acetate metabolism, suggesting its potential as an auxiliary energy substrate. In hiPSC-derived astrocytes, AD-specific metabolic responses to C10 varied by mutation, with only partial alterations in oxidative glucose metabolism observed in APP and PSEN1 variants, highlighting genotype-dependent metabolic alterations. While AD-related mutations in the hiPSC models did not lead to robust deficits, the in vivo environment in the 5xFAD model is associated with measurable metabolic changes in astrocytes. These findings underscore astrocytic metabolic dysfunction in AD and suggest that C10 supplementation may restore brain energy by supporting astrocytic oxidative metabolism. Full article

(This article belongs to the Section Cellular Metabolism)

► Show Figures

Graphical abstract

34 pages, 1894 KB

Open AccessReview

Oncolytic Virotherapy in Colorectal Cancer: Mechanistic Insights, Enhancer Strategies, and Translational Combinations

by Huda Salameh, Nesha Naseem, Muhammad A. Chattha, Joytish Ramesh, Haneen Ramy, Dasa Cizkova, Peter Kubatka and Dietrich Büsselberg

Cells 2025, 14(24), 2006; https://doi.org/10.3390/cells14242006 - 16 Dec 2025

Viewed by 1029

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, with most patients, especially those with microsatellite-stable disease, having limited treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic modality due to their ability to selectively [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of cancer-related morbidity and mortality worldwide, with most patients, especially those with microsatellite-stable disease, having limited treatment options. Oncolytic viruses (OVs) have emerged as a promising therapeutic modality due to their ability to selectively replicate in malignant cells and mediate antitumor effects through direct oncolysis, immune activation, and modulation of tumor angiogenesis. This review analyzed 101 primary studies that reported the use of OV in CRC. The extracted data, including virus type, study design, model system, mechanistic pathways, and therapeutic strategies, were organized as standalone therapy, combination therapy, or enhancer-based approaches. Across studies, OV monotherapy consistently induced selective tumor cell lysis and, in some models, also exhibited additional immunogenic and anti-angiogenic effects. Combination strategies, particularly those with immune checkpoint inhibitors, demonstrated synergistic activity, enhancing T-cell infiltration, cytokine production, and tumor control even in resistant CRC settings. Enhancer approaches, including mesenchymal stem cell delivery systems and tumor-specific promoters, have improved viral selectivity, tumor penetration, and reduced immune clearance. Despite promising findings, progress is hindered by heterogeneous models and the scarcity of advanced clinical trials. Translation into well-designed clinical studies is now warranted to optimize therapeutic outcomes. Full article

(This article belongs to the Special Issue Gastrointestinal Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Graphical abstract

20 pages, 11183 KB

Open AccessArticle

The Cell Polarity Protein Scribble Is Involved in Maintaining the Structure of Neuromuscular Junctions, the Expression of Myosin Heavy Chain Genes, and Endocytic Recycling in Adult Skeletal Muscle Fibers

by Lea Gessler, Yongzhi Jian, Nam Anh Ngo and Said Hashemolhosseini

Cells 2025, 14(24), 2005; https://doi.org/10.3390/cells14242005 - 16 Dec 2025

Viewed by 1209

Abstract

The role of LAP proteins expressed in skeletal muscles (ERBIN, LANO, and SCRIBBLE) and at neuromuscular junctions (NMJs) remains largely unknown. Our previous data demonstrate that LAP proteins are differentially expressed in muscle cells, nerve endings, and terminal Schwann cells, though they are [...] Read more.

The role of LAP proteins expressed in skeletal muscles (ERBIN, LANO, and SCRIBBLE) and at neuromuscular junctions (NMJs) remains largely unknown. Our previous data demonstrate that LAP proteins are differentially expressed in muscle cells, nerve endings, and terminal Schwann cells, though they are all expressed in myofibers and accumulate at NMJs. ERBIN and SCRIBBLE align with acetylcholine receptor clusters (CHRNs) at the NMJ. In vivo ablation of Erbin is associated with smaller CHRN and upregulation of Lano and Scribble. However, SCRIBBLE was also shown to influence the fate decision of muscle stem cells. Here, we investigated how the absence of SCRIBBLE in skeletal muscle cells might impair skeletal muscle fibers or NMJs. Although conditional Scribble knockout mice did not exhibit changes in weight or viability, force per weight decreased slightly. This was supported by compromised neuromuscular transmission and increased NMJ fragmentation. Moreover, Scribble knockout muscles transcribe less myosin heavy chain genes. Here, we also showed that RAB5, an effector of endocytic recycling, interacts with all LAP proteins, but in Scribble knockout muscles, reduced interaction was detected with ERBIN and LANO. These data suggest that a delicate signaling network employing LAP proteins is necessary for skeletal muscle fibers and NMJs. Full article

(This article belongs to the Section Cell Signaling)

► Show Figures

Graphical abstract

15 pages, 3250 KB

Open AccessArticle

Sibling-Derived Cell Lines of Whole Larval Siberian Sturgeon as an In Vitro Model System for Studying Inter-Individual Differences Within the Same Genomic Heritage

by Valeria Di Leonardo, Katrin Tönißen, Julia Brenmoehl, Daniela Ohde, Heike Wanka, Kenneth Benning and Bianka Grunow

Cells 2025, 14(24), 2004; https://doi.org/10.3390/cells14242004 - 16 Dec 2025

Viewed by 465

Abstract

Sturgeons, once resilient enough to outlive dinosaurs, are now critically endangered. All 26 species of Acipenseriformes face extinction due to anthropogenic causes. Despite their ecological and economic significance, sturgeon research lacks essential tools such as larval cell lines; the Cellosaurus database lists only [...] Read more.

Sturgeons, once resilient enough to outlive dinosaurs, are now critically endangered. All 26 species of Acipenseriformes face extinction due to anthropogenic causes. Despite their ecological and economic significance, sturgeon research lacks essential tools such as larval cell lines; the Cellosaurus database lists only one larval cell line (AOXlar7y from Atlantic sturgeon). Larval stages are key to understand fish development, representing a transitional phase between embryonic and adult life that is highly sensitive to temperature shifts, oxygen depletion and pollution. Larval cell lines therefore provide potential in vitro models for studying development and stress responses in endangered species. This study focused on establishing and initially characterizing five novel larval cell lines from siblings of the Siberian sturgeon (Acipenser baerii). The lines proved viable for long-term culture, bio-banking and transfer, displaying different morphologies ranging from epithelial-like to fibroblast-like. Functional assays showed variable mitochondrial activity and extracellular acidification rates. A preliminary targeted gene expression analysis revealed similarity to whole larvae within early passages and in vitro adaptations for certain genes (gapdh, vim, col1a1, pcna). These sibling-derived cell lines hold potential as in vitro tools to deeper explore the biology of Siberian sturgeon larvae and support conservation-focused research. Full article

► Show Figures

Graphical abstract

18 pages, 2378 KB

Open AccessArticle

Impact of the etr1-1 Mutation, Impairing Ethylene Sensitivity, on Hormonal Status and Growth of Arabidopsis thaliana Under Salinity Stress

by Anna Sevostyanova, Alla Korobova, Guzel Akhiyarova, Igor Ivanov and Guzel Kudoyarova

Cells 2025, 14(24), 2003; https://doi.org/10.3390/cells14242003 - 16 Dec 2025

Cited by 1 | Viewed by 461

Abstract

The role of ethylene in the adaptation of Arabidopsis thaliana to salt stress induced by 150 mM NaCl is investigated. The responses of wild-type (Columbia, WT) plants and ethylene-insensitive etr1-1 mutants to short-term daily salt treatments were compared. Parameters analyzed included growth, water [...] Read more.

The role of ethylene in the adaptation of Arabidopsis thaliana to salt stress induced by 150 mM NaCl is investigated. The responses of wild-type (Columbia, WT) plants and ethylene-insensitive etr1-1 mutants to short-term daily salt treatments were compared. Parameters analyzed included growth, water status, chlorophyll content, and hormone levels (ABA, IAA, cytokinins) using ELISA and immunohistochemistry. The results revealed that in the WT, salt stress induced hormonal redistribution: accumulation of ABA, IAA, and zeatin in shoots, accompanied by decreased ABA in the root tips and cytokinins in the whole roots. These hormonal changes were associated with stomatal closure, maintained leaf hydration, and inhibition of root growth. The inhibition of root growth may contribute to reduced uptake of toxic ions from the environment. In contrast, etr1-1 mutants exhibited no changes in hormonal status, failed to close stomata—leading to decreased leaf water content—and showed a sharp decline in chlorophyll content accompanied by suppressed shoot growth. The conclusions emphasize that ethylene sensitivity is essential for initiating adaptive hormonal rearrangements that coordinate growth and stomatal responses to mitigate the effects of salt stress. Full article

(This article belongs to the Section Plant, Algae and Fungi Cell Biology)

► Show Figures

Figure 1

27 pages, 3096 KB

Open AccessArticle

B Cells Can Trigger the T-Cell-Mediated Autoimmune Response Against Melanocytes in Psoriasis

by Mengwen He, Melissa Bernhardt, Akiko Arakawa, Song-Min Kim, Sigrid Vollmer, Burkard Summer, Yukiyasu Arakawa, Tatsushi Ishimoto, Andreas Schlosser and Jörg Christoph Prinz

Cells 2025, 14(24), 2002; https://doi.org/10.3390/cells14242002 - 16 Dec 2025

Cited by 2 | Viewed by 1096

Abstract

Psoriasis vulgaris is a T-cell-mediated skin disease that may involve an autoimmune response against melanocytes. It develops through still unexplained pathomechanisms. Streptococcal tonsillopharyngitis is a major trigger of psoriasis onset and relapses. HLA-C*06:02 is the main psoriasis risk gene. Here we find that [...] Read more.

Psoriasis vulgaris is a T-cell-mediated skin disease that may involve an autoimmune response against melanocytes. It develops through still unexplained pathomechanisms. Streptococcal tonsillopharyngitis is a major trigger of psoriasis onset and relapses. HLA-C*06:02 is the main psoriasis risk gene. Here we find that B cells isolated from streptococci-infected tonsils or peripheral blood of HLA-C*06:02⁺ psoriasis patients stimulate an HLA-C*06:02-restricted melanocyte-reactive Vα3S1/Vβ13S1 T-cell receptor (TCR) from a lesional psoriatic CD8⁺ T cell clone in an IFN-γ-enhanced manner. Patients’ B cells furthermore induce proliferation of autologous blood CD8⁺ T cells. We identify several HLA-C*06:02-presented self-peptides in the immunopeptidomes we had isolated from four HLA-C*06:02 homozygous B-cell lines that stimulate the Vα3S1/Vβ13S1 TCR and differ from the melanocyte autoantigen recognized by this TCR. These data suggest that the proinflammatory environment of streptococcal tonsillopharyngitis may enable B cells to activate autoreactive CD8⁺ T cells that, owing to the polyspecificity of T-cell receptors, recognize several B-cell self-peptides presented by HLA-C*06:02 and subsequently cross-react against melanocytes in the skin, thereby triggering psoriasis. The capacity of B cells to stimulate a cross-reactive autoimmune response through HLA class I-presented B-cell peptides is a previously unknown mechanism in the induction of autoimmunity that could explain psoriasis onset and persistence. Full article

(This article belongs to the Special Issue Genetic and Cellular Basis of Autoimmune Diseases)

► Show Figures

Graphical abstract

27 pages, 4795 KB

Open AccessReview

Graphene and Its Derivatives as Modulators of Macrophage Polarization in Cutaneous Wound Healing

by Iwona Lasocka, Michał Skibniewski, Iwona Pasternak, Anna Wróblewska, Zuzanna Biernacka, Ewa Skibniewska, Lidia Szulc-Dąbrowska and Marie Hubalek Kalbacova

Cells 2025, 14(24), 2001; https://doi.org/10.3390/cells14242001 - 16 Dec 2025

Cited by 1 | Viewed by 807

Abstract

Graphene-based materials (GBMs), owing to their excellent biomedical properties, can significantly advance the development of nano-biodressings. Their unique physicochemical features, such as high surface area, tunable functionalization, antimicrobial activity, and ability to interact with immune cells, suggest that GBMs may influence key biological [...] Read more.

Graphene-based materials (GBMs), owing to their excellent biomedical properties, can significantly advance the development of nano-biodressings. Their unique physicochemical features, such as high surface area, tunable functionalization, antimicrobial activity, and ability to interact with immune cells, suggest that GBMs may influence key biological processes involved in tissue repair, particularly the immune response. Building on this growing evidence, the aim of this review is to demonstrate that GBMs can serve as tools for modulating macrophage polarization as a strategy for promoting wound healing. We present the mechanisms by which GBMs penetrate macrophages and discuss the effects of GBMs, either in suspension or as scaffolds/grounds/substrates, on macrophage polarization. Moreover, we propose mechanisms underlying the actions of different forms of GBMs on macrophage polarization. Nevertheless, a multitude of uncertainties and significant challenges remain. Chief among these are the pronounced heterogeneity of GBM subtypes, the necessity for exhaustive characterization and in-depth analysis, the formulation of robust experimental designs, and the careful selection of models capable of accurately delineating macrophage populations and guiding their polarization toward achieving targeted wound healing outcomes. This review attempts to systematize and clarify these issues. Full article

(This article belongs to the Section Cellular Immunology)

► Show Figures

Graphical abstract

3 pages, 144 KB

Open AccessEditorial

Current Status and Future Challenges of Liquid Biopsy

by Shuta Ohara and Kenichi Suda

Cells 2025, 14(24), 2000; https://doi.org/10.3390/cells14242000 - 16 Dec 2025

Viewed by 653

Abstract

Liquid biopsy has rapidly advanced as an innovative tool in precision oncology, allowing clinicians to capture the dynamic molecular and/or quantitative changes in tumors with minimal invasiveness [...] Full article

(This article belongs to the Special Issue Current Status and Future Challenges of Liquid Biopsy)

15 pages, 1474 KB

Open AccessArticle

Piezo1 Mechanosensor Expression in Rare Hematopoietic Cells Controls Systemic Inflammatory Response in Mice

by Shiv Vardan Singh, Anastasia Iris Karkempetzaki, Nasi Huang, Vipul C. Chitalia, Saravanan Subramaniam and Katya Ravid

Cells 2025, 14(24), 1999; https://doi.org/10.3390/cells14241999 - 16 Dec 2025

Viewed by 632

Abstract

Mutations in the Piezo1 mechanosensor are associated with blood cell anomalies. The objective of our study was to explore the role of Piezo1 in the development and function of the megakaryocyte (MK) lineage. To this end, PF4-Cre mice, bearing Cre recombinase under the [...] Read more.

Mutations in the Piezo1 mechanosensor are associated with blood cell anomalies. The objective of our study was to explore the role of Piezo1 in the development and function of the megakaryocyte (MK) lineage. To this end, PF4-Cre mice, bearing Cre recombinase under the control of the Pf4 gene promoter—which drives expression to hematopoietic progenitors and to the MK/platelet lineage—were crossbred with Piezo1-floxed mice to generate Piezo1 knockout (KO) mice. In our results, the hematopoietic stem cell (HSC) count—including Multipotent Progenitors 2 (MPP2) progenitors that give rise to MKs—tended to be augmented in KO mice, while the level of MPP3 progenitors that give rise to white blood cells (WBCs) tended to be reduced, as compared to matching controls. The level of circulating WBCs was significantly reduced in the KO mice compared to controls. In addition, while platelet count was modestly elevated, platelet activation response was reduced in Piezo1 KO mice compared to controls. MK levels and ploidy were similar in both groups. Baseline serum pro-and anti-inflammatory cytokine profiles were also similar in the two experimental groups. However, upon LPS challenge, there was a significant reduction in IL-6 and INF-γ levels in the sera of Piezo1 KO mice compared to controls. Our findings point to an immunoregulatory and thrombotic potential of Piezo1 in relatively rare bone marrow cells, along with an ability to modulate WBC count. Full article

(This article belongs to the Section Cell Microenvironment)

► Show Figures

Graphical abstract

19 pages, 6236 KB

Open AccessArticle

Sequential Inflammatory and Matrisome Programs Drive Remodeling of the Mouse Carotid–Jugular Arteriovenous Fistula

by Filipe F. Stoyell-Conti, Alexander M. Kaiser, Miguel G. Rojas, Yuntao Wei, Matthew S. Sussman, Juan S. Lopez-McCormick, Marwan Tabbara, Xiaofeng Yang, Roberto I. Vazquez-Padron and Laisel Martinez

Cells 2025, 14(24), 1998; https://doi.org/10.3390/cells14241998 - 16 Dec 2025

Viewed by 922

Abstract

The mouse carotid–jugular arteriovenous fistula (AVF) is a widely adopted surgical model to study venous remodeling after AVF creation. Despite its increasing use, the extent to which this model recapitulates the cellular and molecular remodeling processes observed in humans remains uncertain, which is [...] Read more.

The mouse carotid–jugular arteriovenous fistula (AVF) is a widely adopted surgical model to study venous remodeling after AVF creation. Despite its increasing use, the extent to which this model recapitulates the cellular and molecular remodeling processes observed in humans remains uncertain, which is essential for validating its translational relevance. Using bulk and single-cell RNA sequencing, we have depicted the transcriptional and cellular evolution of the mouse jugular vein after AVF anastomosis. Global transcriptomic profiling revealed that venous remodeling begins with a robust inflammatory response, followed by a prominent extracellular matrix (ECM) remodeling phase that peaks at postoperative day 10. Single-cell analyses confirmed the role of macrophage (3-fold) and neutrophil infiltration (12-fold) in sustaining the onset of venous remodeling. These monocytes/macrophages exhibited marked upregulation of pro-inflammatory and pro-fibrotic genes, including Il1b, Spp1, Fn1, Thbs1, and Tgfb1. Evidence of the differentiation of fibroblasts into myofibroblasts positive for Postn, Col8a1, and Thbs1 emerged by postoperative day 5. The temporal dynamics of differentially expressed genes in these myofibroblasts closely mirrored the ECM gene expression patterns identified by bulk RNA-seq, indicating that they are the principal source of ECM deposition in the AVF. Cell-to-cell communication analyses highlighted macrophages and fibroblasts as the main populations driving postoperative remodeling. Comparative analysis with single-cell data from human pre-access veins and AVFs demonstrated that the mouse model reproduces the core inflammatory–fibrotic axis of fibroblast activation observed in humans, supporting its utility for mechanistic studies of postoperative ECM remodeling. Full article

(This article belongs to the Topic Application of Animal Models: From Physiology to Pathology)

► Show Figures

Graphical abstract

31 pages, 8584 KB

Open AccessReview

Next-Generation HDAC Inhibitors: Advancing Zinc-Binding Group Design for Enhanced Cancer Therapy

by Mohammed Hawash

Cells 2025, 14(24), 1997; https://doi.org/10.3390/cells14241997 - 15 Dec 2025

Cited by 2 | Viewed by 977

Abstract

Histone deacetylases (HDACs) are pivotal epigenetic regulators that control gene expression, cell proliferation, and differentiation, and their dysregulation is closely associated with the onset and progression of multiple cancers. The therapeutic importance of these enzymes is reflected by FDA approval of HDAC inhibitors [...] Read more.

Histone deacetylases (HDACs) are pivotal epigenetic regulators that control gene expression, cell proliferation, and differentiation, and their dysregulation is closely associated with the onset and progression of multiple cancers. The therapeutic importance of these enzymes is reflected by FDA approval of HDAC inhibitors for oncology indications. Despite this clinical success, most FDA-approved agents employ conventional zinc-binding groups (ZBGs) such as hydroxamic acid and 2-aminoanilide, which are frequently linked to metabolic instability, genotoxicity, and poor pharmacokinetic behavior. These limitations have spurred the development of structurally diverse and safer HDAC inhibitors incorporating alternative ZBGs. This review provides a comprehensive analysis of recently developed HDAC inhibitors reported in the last few years, emphasizing their structure–activity relationships (SARs), chemical scaffolds, and binding features—including cap, linker, and ZBG motifs. Both hydroxamate-based and non-hydroxamate inhibitors, such as benzamides, hydrazides, and thiol-containing analogs, are critically evaluated. Moreover, the potency and selectivity profiles of these inhibitors are summarized across different cancer and normal cell lines, as well as specific HDAC isoforms, providing a clearer understanding of their therapeutic potential. Emerging dual-target HDAC inhibitors, such as HDAC–tubulin, HDAC–PI3K and HDAC–CDK hybrids, are also discussed for their synergistic anticancer effects. Full article

(This article belongs to the Special Issue Small Molecule Inhibitors: A New Era in Cancer Treatment)

► Show Figures

Figure 1

21 pages, 817 KB

Open AccessSystematic Review

Cellular and Molecular Mechanisms of Non-Invasive Brain Stimulation Techniques: A Systematic Review on the Implications for the Treatment of Neurological Disorders

by Valerio Sveva, Marco Mancuso, Alessandro Cruciani, Elias Paolo Casula, Giorgio Leodori, Silvia Antonella Selvaggi, Matteo Bologna, Vincenzo Di Lazzaro, Anna Latorre and Lorenzo Rocchi

Cells 2025, 14(24), 1996; https://doi.org/10.3390/cells14241996 - 15 Dec 2025

Cited by 1 | Viewed by 1224

Abstract

Non-invasive brain stimulation (NIBS) techniques—including repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS)—have emerged as valuable tools for modulating neural activity and promoting plasticity. Traditionally, their effects have [...] Read more.

Non-invasive brain stimulation (NIBS) techniques—including repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS)—have emerged as valuable tools for modulating neural activity and promoting plasticity. Traditionally, their effects have been interpreted within a binary framework of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity, largely inferred from changes in motor evoked potentials (MEPs). However, existing models do not fully capture the complexity of the biological processes engaged by these techniques and despite extensive clinical application, the cellular and molecular mechanisms underlying NIBS remain only partially understood. This systematic review, conducted in accordance with the PRISMA 2020 guidelines, synthesizes evidence from in vivo, in vitro, and ex vivo studies to delineate how NIBS influences neurotransmission through intracellular signaling, gene expression, and protein synthesis at the cellular level. Emphasis is placed on the roles of classical synaptic models, grounded in Ca²⁺-dependent glutamatergic signaling and receptor phosphorylation dynamics, as well as broader forms of plasticity involving BDNF–TrkB signaling, epigenetic modifications, neuroimmune and glial interactions, anti-inflammatory pathways, and apoptosis- and survival-related cascades. By integrating findings in humans with those in animal and cellular models, we identify both shared and technique-specific molecular mechanisms underlying NIBS-induced effects, highlighting emerging evidence for multi-pathway, non-binary plasticity mechanisms. Understanding these convergent pathways provides a mechanistic foundation for refining stimulation paradigms and improving their translational relevance for treatment of neurological and psychiatric disorders. Full article

(This article belongs to the Special Issue Biological Mechanisms in the Treatment of Neuropsychiatric Diseases)

► Show Figures

Figure 1

16 pages, 5182 KB

Open AccessArticle

Macrophage-Derived Exosomal MALAT1 Induced by Hyperglycemia Regulates Vascular Calcification Through miR-143-3p/MGP Axis in Cultured Vascular Smooth Muscle Cells and Diabetic Rat Carotid Artery

by Kou-Gi Shyu, Bao-Wei Wang, Wei-Jen Fang and Chun-Ming Pan

Cells 2025, 14(24), 1995; https://doi.org/10.3390/cells14241995 - 15 Dec 2025

Viewed by 580

Abstract

Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) is associated with vascular calcification and diabetes-related complications. However, the effect of exosomal MALAT1 derived from macrophages induced by hyperglycemia on vascular calcification (VC) remains unclear. In this study, we investigated the effect of VC and its regulatory [...] Read more.

Metastasis-associated lung adenocarcinoma transcript 1(MALAT1) is associated with vascular calcification and diabetes-related complications. However, the effect of exosomal MALAT1 derived from macrophages induced by hyperglycemia on vascular calcification (VC) remains unclear. In this study, we investigated the effect of VC and its regulatory mechanisms in cultured vascular smooth muscle cells (VSMCs) and diabetic rats by exosomal MALAT1 derived from macrophages treated with high levels of glucose. Macrophages and VSMCs were cultured in 25 mM glucose. Macrophages exposed to high glucose exhibited increased expression of exosomal MALAT1. When transferred to VSMCs, exosomal MALAT1 significantly suppressed the expression of miR-143-3p while upregulating Matrix Gla protein (MGP, an inhibitor of VC) mRNA and protein levels. Interventions using MALAT1 siRNA or miR-143-3p mimics effectively reversed this effect. Both MALAT1 siRNA and overexpression of miR-143-3p significantly increased the calcium content in cultured VSMCs and in the carotid artery of diabetic rats following balloon injury. Balloon injury to the carotid artery in diabetic rats treated with macrophage-derived exosomes significantly increased the expression of MALAT1 and MGP while reducing the expression of miR-143-3p in the carotid artery. These findings demonstrate that macrophage-derived exosomal MALAT1 modulates VC via the MALAT1/miR-143-3p/MGP axis under hyperglycemic conditions. The results suggest that targeting exosomal MALAT1 may offer a novel and effective therapeutic approach for mitigating VC in metabolic disorders such as diabetes. Full article

► Show Figures

Graphical abstract

23 pages, 3502 KB

Open AccessReview

Modeling Drug and Radiation Resistance with Patient-Derived Organoids: Recent Progress, Unmet Needs, and Future Directions for Lung Cancer

by Dahye Lee, Yoonjoo Kim, Da Hyun Kang and Chaeuk Chung

Cells 2025, 14(24), 1994; https://doi.org/10.3390/cells14241994 - 15 Dec 2025

Cited by 1 | Viewed by 1079

Abstract

Background: Chemotherapy, targeted therapy and radiotherapy are the cornerstones of cancer treatment. However, therapeutic resistance—not only to these classic modalities but also to novel therapeutics like immune checkpoint inhibitors (ICIs) and antibody-drug conjugates—remains a major hurdle. Resistance significantly limits efficacy and increases recurrence [...] Read more.

Background: Chemotherapy, targeted therapy and radiotherapy are the cornerstones of cancer treatment. However, therapeutic resistance—not only to these classic modalities but also to novel therapeutics like immune checkpoint inhibitors (ICIs) and antibody-drug conjugates—remains a major hurdle. Resistance significantly limits efficacy and increases recurrence rates. A deep understanding of the molecular mechanisms driving this resistance is critical for developing personalized therapeutic strategies and improving patient outcomes. Recent Advances: Patient-derived cancer organoids have emerged as a powerful preclinical platform that faithfully recapitulates the genetic, phenotypic, and histological characteristics of original tumors. Consequently, PDOs are being widely utilized to evaluate drug responses, investigate resistance mechanisms, and discover novel therapeutic targets for a range of therapies. Limitations: While organoid models have been instrumental in studying resistance, significant limitations persist. First, standard organoid-only models lack key tumor microenvironment components, such as immune cells, limiting immunotherapy research. Second, there is a significant lack of research on acquired resistance, particularly in lung cancer. This gap is largely driven by the clinical infeasibility of rebiopsy in patients with progressive diseases. Third, the absence of standardized protocols for generating and validating resistance models hinders reproducibility and complicates clinical translation. Conclusions: This review summarizes recent advances in using organoid models to study resistance to chemotherapy, radiotherapy, and novel therapeutics (ICIs and ADCs). We emphasize the critical need for standardization in resistance organoid research. We also propose future directions to overcome existing challenges, including the integration of co-culture systems (to include the TME) and advanced technologies (e.g., scRNA-seq, Spatial Transcriptomics). Our specific focus is on advancing lung cancer resistance modeling to enable functional precision medicine. Full article

(This article belongs to the Special Issue Recent Advances in Microfluidics and Organoids for Biomedical Applications)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Cells, Volume 14, Issue 24 (December-2 2025) – 93 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI