Cells

24 pages, 3035 KiB

Open AccessArticle

Functional Characterization of LTR12C as Regulators of Germ-Cell-Associated TA-p63 in U87-MG and T98-G In Vitro Models

by Lucia Meola, Sohum Rajesh Shetty, Angelo Peschiaroli, Claudio Sette and Camilla Bernardini

Cells 2025, 14(11), 852; https://doi.org/10.3390/cells14110852 - 5 Jun 2025

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Glioblastoma multiforme (GBM) is a deadly disease known for its genetic heterogeneity. LTR12C is an endogenous retrovirus-derived regulator of pro-apoptotic genes and is normally silenced by epigenetic regulation. In this study, we found that the treatment of two glioblastoma cell lines, T98-G and [...] Read more.

Glioblastoma multiforme (GBM) is a deadly disease known for its genetic heterogeneity. LTR12C is an endogenous retrovirus-derived regulator of pro-apoptotic genes and is normally silenced by epigenetic regulation. In this study, we found that the treatment of two glioblastoma cell lines, T98-G and U87-MG, with DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors activated LTR12C expression. Combined treatment with these epigenetic drugs exerted a synergistic action on the LTR12C activation in both cell lines, while treatment with each drug as a single agent had a far weaker effect. A strong induction of the expression of the TP63 gene was seen in both cell lines, with the pro-apoptotic isoform GTA-p63 accounting for most of this increase. Coherently, downstream targets of p63, such as p21 and PUMA, were also induced by the combined treatment. Furthermore, we observed a significant reduction in the GBM cell growth and viability following the dual DNMT/HDAC inhibition. These findings reveal that the reactivation of LTR12C expression has the potential to modulate survival pathways in glioblastoma and provide information regarding possible epigenetic mechanisms that can be used to treat this deadly disease. Full article

(This article belongs to the Section Cell and Gene Therapy)

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14 pages, 1973 KiB

Open AccessArticle

Mesenchymal Stem Cell Secretome Attenuates PrP^106-126-Induced Neurotoxicity by Suppressing Neuroinflammation and Apoptosis and Enhances Cell Migration

by Mohammed Zayed and Byung-Hoon Jeong

Cells 2025, 14(11), 851; https://doi.org/10.3390/cells14110851 - 5 Jun 2025

Viewed by 365

Abstract

Prion diseases are disorders caused by the misfolding of prion protein (PrP^Sc), leading to the accumulation of an abnormal form of the normal prion protein (PrP) found in the host. The secretome of mesenchymal stem cells (MSCs), including paracrine-soluble factors, holds [...] Read more.

Prion diseases are disorders caused by the misfolding of prion protein (PrP^Sc), leading to the accumulation of an abnormal form of the normal prion protein (PrP) found in the host. The secretome of mesenchymal stem cells (MSCs), including paracrine-soluble factors, holds promising potential to stimulate host regenerative capability and alleviate organ disorders. In this research, our goal was to investigate the neuroprotective properties of the secretome derived from adipose-derived mesenchymal stem cells (AdMSC secretome) in relation to the toxicity caused by PrP^106−126 in SH-SY5Y cells. The findings showed that PrP^106−126 treatment exacerbated the neurotoxicity of SH-SY5Y cells, as indicated by increased lactate dehydrogenase (LDH) release. However, the AdMSC secretome significantly decreased LDH release. Under PrP^106−126 stimulation, the AdMSC secretome downregulated inflammatory markers (TNF-α and IL-1β) and upregulated anti-inflammatory IL-10. Treatment with the AdMSC secretome markedly reduced GFAP immunoreactivity in astrocytic C8D1A cells compared to treatment with PrP^106−126 alone. In addition, the AdMSC secretome reduced Iba-1 immunoreactivity in BV2 cells activated by LPS. Western blot analysis showed that the AdMSC secretome inhibited pro-apoptotic factor Bax induced by PrP^106−126 and increased the expression of anti-apoptotic factor Bcl-2. However, no significant difference was observed in the expression of caspase-3. The AdMSC secretome exhibited a considerable migratory effect on SH-SY5Y cells after 24 h, as demonstrated by the scratch assay. The results suggest that the AdMSC secretome can attenuate PrP^106−126-induced neuronal damage. Full article

(This article belongs to the Special Issue Neurotoxicity and Neurodegenerative Diseases: The Potential of Regenerative Medicine)

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20 pages, 1713 KiB

Open AccessReview

Rosmarinic Acid as Bioactive Compound: Molecular and Physiological Aspects of Biosynthesis with Future Perspectives

by Dragana Jakovljević, Marzena Warchoł and Edyta Skrzypek

Cells 2025, 14(11), 850; https://doi.org/10.3390/cells14110850 - 5 Jun 2025

Viewed by 351

Abstract

The ester of caffeic acid with α-hydroxydihydrocaffeic acid, named rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) can occur as oligomeric molecules, or in free, esterified, and glycosidic forms. Although it is commonly found among the members of the plants from the Lamiaceae (mints) and Boraginaceae [...] Read more.

The ester of caffeic acid with α-hydroxydihydrocaffeic acid, named rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) can occur as oligomeric molecules, or in free, esterified, and glycosidic forms. Although it is commonly found among the members of the plants from the Lamiaceae (mints) and Boraginaceae (borages) families, only certain plant species produce a comparatively high concentration of RA. This valuable bioactive compound exhibits anti-cancer, anti-angiogenic, antioxidant, anti-inflammatory, antiviral, and antimicrobial properties, among others. As it is difficult to obtain high quantities of RA from natural sources, and since chemical manufacturing is costly and challenging, various biotechnological methods have recently been investigated to boost RA production. Plant cell tissue culture has been used to promote RA production in various plant species, particularly medicinal ones, with elicitation being the most commonly used technique. This review explores the main steps involved in RA biosynthesis in plants, including the molecular mechanisms and physiological alterations underlying its function, along with the primary mechanisms of RA accumulation in response to elicitation. Recent progress in synthetic biology-based RA synthesis, as well as metabolic engineering techniques to enhance the industrial production of this valuable bioactive constituent, are also discussed. Full article

(This article belongs to the Special Issue Antioxidants in Redox Homeostasis of Plant Development)

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15 pages, 1782 KiB

Open AccessArticle

HSP110 Regulates the Assembly of the SWI/SNF Complex

by Océane Pointeau, Manon Paccagnini, Natalia Borges-Bonan, Léo Biziorek, Sébastien Causse, Carmen Garrido and Laurence Dubrez

Cells 2025, 14(11), 849; https://doi.org/10.3390/cells14110849 - 5 Jun 2025

Viewed by 328

Abstract

HSP110 is a ubiquitous chaperone contributing to proteostasis. It has a disaggregation activity and can refold denatured proteins. It can regulate fundamental signaling pathways involved in oncogenesis, such as Wnt/β-catenin, NF-κB and STAT3 signaling pathways. In gastric and colorectal cancer, HSP110 has been [...] Read more.

HSP110 is a ubiquitous chaperone contributing to proteostasis. It has a disaggregation activity and can refold denatured proteins. It can regulate fundamental signaling pathways involved in oncogenesis, such as Wnt/β-catenin, NF-κB and STAT3 signaling pathways. In gastric and colorectal cancer, HSP110 has been detected in the nucleus, and nuclear expression has been associated with the resistance of cells to 5-FU chemotherapy. Nuclear translocation of HSP110 is promoted by the exposure of cells to DNA-damaging agents. In a previous work, we demonstrated that nuclear HSP110 participates in the NHEJ DNA repair pathway by facilitating the recruitment of DNA-PKcs to Ku70/80 heterodimers at the site of DNA double-strand breaks. In the present work, analysis of HSP110s’ nuclear interactome revealed an enrichment of components from SWI/SNF chromatin remodeling complexes. We demonstrate that HSP110 is strongly associated with chromatin in temozolomide- and oxaliplatin-treated cells and directly interacts with the core subunit SMARCC2, thereby facilitating the assembly of SWI/SNF complexes. This work expands upon the role of HSP110, which regulates not only proteostasis but also the assembly of critical nuclear macromolecular complexes involved in the adaptive stress response. Full article

(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)

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23 pages, 1309 KiB

Open AccessReview

Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis

by Lorena Pisoni, Luisa Donini, Paola Gagni, Maria Pennuto, Antonia Ratti, Federico Verde, Nicola Ticozzi, Jessica Mandrioli, Andrea Calvo and Manuela Basso

Cells 2025, 14(11), 848; https://doi.org/10.3390/cells14110848 - 5 Jun 2025

Viewed by 608

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction. Full article

(This article belongs to the Special Issue Motor Neuron Diseases: From Molecular Basic Research to Diagnosis and Therapeutics Implications)

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14 pages, 1475 KiB

Open AccessReview

Spatial Eosinophil Phenotypes as Immunopathogenic Determinants in Inflammatory Diseases

by Jonas S. Erjefält

Cells 2025, 14(11), 847; https://doi.org/10.3390/cells14110847 - 5 Jun 2025

Viewed by 421

Abstract

Eosinophils are increasingly recognized as adaptable immune cells that exhibit diverse phenotypes and effector functions across different tissues and disease states. While they can induce pathology through degranulation and cytotoxic mediator release, eosinophils also fulfill regulatory and tissue repair roles. Advances in single-cell [...] Read more.

Eosinophils are increasingly recognized as adaptable immune cells that exhibit diverse phenotypes and effector functions across different tissues and disease states. While they can induce pathology through degranulation and cytotoxic mediator release, eosinophils also fulfill regulatory and tissue repair roles. Advances in single-cell and spatial technologies have begun to reveal how microenvironmental cues (including cytokines, chemokines, and cell–cell interactions) shape eosinophil behavior in health and disease. These insights are critical for understanding why certain patients respond variably to therapies targeting eosinophils and related type 2 pathways. By dissecting eosinophil heterogeneity in real human tissues, researchers may identify new biomarkers, refine endotyping approaches, and develop more precise therapeutic strategies. This review summarizes emerging concepts of eosinophil biology in inflammatory conditions, highlights the impact of spatial context on eosinophil functions, and discusses the future of advanced phenotyping in guiding personalized treatments. Full article

(This article belongs to the Special Issue Eosinophils and Their Role in Allergy and Related Diseases)

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28 pages, 1932 KiB

Open AccessReview

Power of Memory: A Natural Killer Cell Perspective

by Oishi Sinha, SK Abhipsha and Sumit Sen Santara

Cells 2025, 14(11), 846; https://doi.org/10.3390/cells14110846 - 5 Jun 2025

Viewed by 600

Abstract

Memory is an incredible aspect of our immune system. Similarly to our cognitive memory, it allows us to remember and respond more efficiently to subsequent encounters with the same pathogens, making it possible to act on the information built by previous experiences. This [...] Read more.

Memory is an incredible aspect of our immune system. Similarly to our cognitive memory, it allows us to remember and respond more efficiently to subsequent encounters with the same pathogens, making it possible to act on the information built by previous experiences. This process is critical for the body’s defenses against infections and is the cornerstone for the effectiveness of vaccines. Immunological memory, traditionally considered an exclusive quality of the adaptive immune system, is a sophisticated component of the immune response system that is characterized by the ability to recognize and remember specific pathogens. This form of memory is primarily observed in antigen-specific T and B cells, which are specialized for recognizing particular antigens and generating a quicker immune response upon each successive reinfection over a long period of time. Natural killer (NK) cells, essential as the body’s first line of defense against a wide range of viral infections and tumors, have traditionally been classified as a key component of the innate immune system, characterized by their lack of antigen specificity and memory. However, the concept of innate vs. adaptive has been evolving, with increasing evidence suggesting that specific cellular subsets of the innate immune system may also play a role in immunological memory. This review aims to provide a comprehensive overview of the recent advances in the understandings of the molecular mechanisms driving the development of memory-like properties in NK cells, with a primary focus on human data in the context of various diseases and infectious conditions. Additionally, we will examine the therapeutic implications of these findings, highlighting how insights into NK cell memory can contribute to the development of novel immunotherapies and improve strategies for treating infections, cancer, and autoimmune disorders. Full article

(This article belongs to the Special Issue Emerging Insights into Natural Killer Cell Immunity in Infection and Cancer)

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17 pages, 995 KiB

Open AccessReview

Broken Balance: Emerging Cross-Talk Between Proteostasis and Lipostasis in Neurodegenerative Diseases

by Jessica Tittelmeier and Carmen Nussbaum-Krammer

Cells 2025, 14(11), 845; https://doi.org/10.3390/cells14110845 - 4 Jun 2025

Viewed by 470

Abstract

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital [...] Read more.

Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease, are characterized by progressive neuronal loss, leading to cognitive and motor impairments. Although these diseases have distinct clinical manifestations, they share pathological hallmarks such as protein aggregation and lysosomal dysfunction. The lysosome plays a vital role in maintaining cellular homeostasis by mediating the degradation and recycling of proteins, lipids, and other macromolecules. As such, it serves as a central hub for both proteostasis and lipostasis. This review outlines genetic and mechanistic parallels between rare lysosomal lipid storage diseases, such as Gaucher disease and Niemann–Pick disease, and more prevalent neurodegenerative diseases. We discuss how impaired lysosomal sphingolipid metabolism compromises lysosomal integrity, disrupts proteostasis, and contributes to neurodegeneration. Furthermore, we describe how age-related decline in lysosomal function may similarly drive neurodegeneration in the absence of overt genetic mutations. Taken together, this review highlights the lysosome as a central integrator of protein and lipid homeostasis and emphasizes the bidirectional relationship between lipostasis and proteostasis, whereby disruption of one adversely affects the other in the pathogenesis of multiple neurodegenerative diseases. Full article

(This article belongs to the Special Issue Protein Misfolding Diseases: From Experimental Approaches to Therapeutic Opportunities)

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21 pages, 1963 KiB

Open AccessArticle

Elevated Mutation Burdens in Canadian Oat and Wheat Cultivars Released over the Past Century

by Yong-Bi Fu and Carolee Horbach

Cells 2025, 14(11), 844; https://doi.org/10.3390/cells14110844 - 4 Jun 2025

Viewed by 245

Abstract

Modern high-yielding crop cultivars are known to have narrow genetic bases, making them vulnerable to biotic and abiotic stresses. However, little is known about the extent of deleterious genetic variants (or mutation burden) present in these cultivars. An attempt was made using RNA-Seq [...] Read more.

Modern high-yielding crop cultivars are known to have narrow genetic bases, making them vulnerable to biotic and abiotic stresses. However, little is known about the extent of deleterious genetic variants (or mutation burden) present in these cultivars. An attempt was made using RNA-Seq to screen genome-wide deleterious genetic variants in 141 oat and 142 wheat cultivars released through Canadian breeding programs over the past century. The screening identified 5726 and 3022 deleterious genetic variants across all 21 chromosomes of both the oat and wheat genomes, respectively. These deleterious variants were largely harbored in a few cultivars and were involved with diverse biological processes, cellular components, and molecular functions. More highly deleterious variants were predicted in oat, than in wheat, cultivars, and different gene expression profiles at the early seedling stage were observed between oat and wheat cultivars, illustrating different genetic impacts of the oat and wheat breeding programs. Estimating mutation burdens for each cultivar revealed large variations among both the oat and wheat cultivars. These mutation burdens were found to increase from early to recent oat and wheat cultivars and were associated with higher cultivar yields. Genetic analyses also revealed genetic shifts and expansions from early to recent oat and wheat cultivars. These findings provide the first empirical evidence of elevated mutation burdens in Canadian oat and wheat cultivars and are useful for advancing plant breeding programs to minimize genetic risk. Full article

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

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28 pages, 2711 KiB

Open AccessArticle

Soluble β-Amyloid Oligomers Selectively Upregulate TRPC3 in Excitatory Neurons via Calcineurin-Coupled NFAT

by Zhengjun Wang, Dongyi Ding, Jiaxing Wang, Ling Chen, Qingming Dong, Moumita Khamrai, Yuyang Zhou, Akihiro Ishii, Kazuko Sakata, Wei Li, Jianyang Du, Thirumalini Vaithianathan, Fu-Ming Zhou and Francesca-Fang Liao

Cells 2025, 14(11), 843; https://doi.org/10.3390/cells14110843 - 4 Jun 2025

Viewed by 525

Abstract

To investigate how dysregulated transient receptor potential canonical channels (TRPCs) are associated with Alzheimer’s disease (AD), we challenged primary neurons with amyloid-β (Aβ). Both the naturally secreted or synthetic Aβ oligomers (AβOs) induced long-lasting increased TRPC3 and downregulated the TRPC6 expression in mature [...] Read more.

To investigate how dysregulated transient receptor potential canonical channels (TRPCs) are associated with Alzheimer’s disease (AD), we challenged primary neurons with amyloid-β (Aβ). Both the naturally secreted or synthetic Aβ oligomers (AβOs) induced long-lasting increased TRPC3 and downregulated the TRPC6 expression in mature excitatory neurons (CaMKIIα-high) via a Ca²⁺-dependent calcineurin-coupled NFAT transcriptionally and calpain-mediated protein degradation, respectively. The TRPC3 expression was also found to be upregulated in pyramidal neurons of human AD brains. The selective downregulation of the Trpc6 gene induced synaptotoxicity, while no significant effect was observed from the Trpc3-targeting siRNA, suggesting potentially differential roles of TRPC3 and 6 in modulating the synaptic morphology and functions. Electrophysiological recordings of mouse hippocampal slices overexpressing TRPC3 revealed increased neuronal hyperactivity upon the TRPC3 channel activation by its agonist. Furthermore, the AβO-mediated synaptotoxicity appeared to be positively correlated with the degrees of the induced dendritic Ca²⁺ flux in neurons, which was completely prevented by the co-treatment with two pyrazole-based TRPC3-selective antagonists Pyr3 or Pyr10. Taken together, our findings suggest that the aberrantly upregulated TRPC3 is another ion channel critically contributing to the process of AβO-induced Ca²⁺ overload, neuronal hyperexcitation, and synaptotoxicity, thus representing a potential therapeutic target of AD. Full article

(This article belongs to the Collection Cell Biology in the United States: Latest Advances and Perspectives)

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35 pages, 1109 KiB

Open AccessReview

Brain Organoids and Assembloids—From Disease Modeling to Drug Discovery

by Aderonke O. Ajongbolo and Sigrid A. Langhans

Cells 2025, 14(11), 842; https://doi.org/10.3390/cells14110842 - 4 Jun 2025

Viewed by 752

Abstract

Brain organoids are self-organized, three-dimensional (3D) aggregates derived from human embryonic stem cells, induced pluripotent stem cells, or primary organs with cell types and cellular architectures resembling those of the developing human brain. Recent studies have shown the use of region-specific brain organoids [...] Read more.

Brain organoids are self-organized, three-dimensional (3D) aggregates derived from human embryonic stem cells, induced pluripotent stem cells, or primary organs with cell types and cellular architectures resembling those of the developing human brain. Recent studies have shown the use of region-specific brain organoids for modeling various diseases ranging from neurodevelopmental and neurodegenerative diseases to different brain cancers, which have numerous applications in fundamental research and the development of new drugs, personalized treatment, and regenerative medicine. Consequently, the use of brain organoids in drug discovery is complex and challenging and still an emerging area in this field. This review article summarizes the primary stem cells used in brain organoid generation, region-specific brain organoids, and the functional assays used in their characterization. In addition, we discuss the use of brain organoids in modeling neurodevelopmental and neurodegenerative diseases and pediatric brain cancers, as well as the application of organoids, assembloids, and tumoroids in cancer neuroscience. We further explore the recent advances in using brain organoids in high-throughput screening to improve their use for drug discovery. Full article

(This article belongs to the Special Issue Organoids as an Experimental Tool)

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16 pages, 10464 KiB

Open AccessArticle

Absence of Microglial Activation and Maintained Hippocampal Neurogenesis in a Transgenic Mouse Model of Crohn’s Disease

by Rebecca Katharina Masanetz, Hanna Mundlos, Iris Stolzer, Jürgen Winkler, Claudia Günther and Patrick Süß

Cells 2025, 14(11), 841; https://doi.org/10.3390/cells14110841 - 4 Jun 2025

Viewed by 527

Abstract

Adult neurogenesis in the hippocampal dentate gyrus (DG) is not only essential for learning and pattern separation, but it is also involved in emotional regulation. This process is vulnerable to local and peripheral inflammation, which is partly mediated by microglia in the DG. [...] Read more.

Adult neurogenesis in the hippocampal dentate gyrus (DG) is not only essential for learning and pattern separation, but it is also involved in emotional regulation. This process is vulnerable to local and peripheral inflammation, which is partly mediated by microglia in the DG. As Crohn’s disease (CD) is associated with neuropsychiatric comorbidity, including depression and cognitive impairment, a reduction in adult hippocampal neurogenesis by chronic gut-derived inflammation has been hypothesized. Here, we present the first study that examined the influence of chronic ileocolitis on microglia in the DG and on adult hippocampal neurogenesis in a transgenic mouse model of CD, which is generated by a constitutive knockout of caspase 8 in intestinal epithelial cells (IECs, Casp8^ΔIEC mice). Structural and transcriptional analyses revealed that microglial cell proliferation and density in the DG as well as the expression of genes associated with their homeostasis and activation in the forebrain were maintained in 14- and 24-week-old Casp8^ΔIEC mice compared to Casp8^fl controls. Furthermore, different stages of adult hippocampal neurogenesis, including progenitor cell proliferation, maturation, and apoptosis of newly generated cells, were predominantly unaffected by chronic ileocolitis, except a potential minor phenotypic shift in maturating cells in 24-week-old mice. Together, we demonstrate largely preserved adult hippocampal neurogenesis, lacking signs of local inflammatory microglial activation despite chronic inflammation of the gut. Full article

(This article belongs to the Special Issue Advances in Neurogenesis: 3rd Edition)

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30 pages, 1307 KiB

Open AccessReview

Electrical Stimulation of Oral Tissue-Derived Stem Cells: Unlocking New Potential for Dental and Periodontal Regeneration

by Rúben S. Pires, Mafalda S. Santos, Filipe Miguel, Cláudia L. da Silva and João Carlos Silva

Cells 2025, 14(11), 840; https://doi.org/10.3390/cells14110840 - 4 Jun 2025

Viewed by 506

Abstract

The tooth and its supporting periodontium are essential structures of the oral cavity, frequently compromised by conditions such as dental defects, aries, and periodontal diseases, which, if poorly treated, often lead to tooth loss. These conditions, affecting billions of people worldwide, remain significant [...] Read more.

The tooth and its supporting periodontium are essential structures of the oral cavity, frequently compromised by conditions such as dental defects, aries, and periodontal diseases, which, if poorly treated, often lead to tooth loss. These conditions, affecting billions of people worldwide, remain significant healthcare and socio-economic challenges. Regenerative dentistry has emerged as a possible therapeutic option, leveraging advances in tissue engineering (TE), stem cell biology, and biophysical stimulation. Oral tissue-derived mesenchymal stem/stromal cells (OMSCs) hold great potential for dental and periodontal regeneration. Electrical stimulation (ES), a biophysical cue known to regulate key cellular behaviors such as migration, proliferation, and differentiation, has gained increasing attention for enhancing the therapeutic capacities of OMSCs. This review explores the biological properties of OMSCs under ES, its role in regenerative dentistry, and recent breakthroughs in ES-based dental and periodontal TE strategies. Furthermore, the current challenges and future directions for translating these innovative approaches into clinical practice are discussed. Full article

(This article belongs to the Special Issue Oral Tissue Stem Cells in Regenerative Dentistry)

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21 pages, 4980 KiB

Open AccessReview

The Interplay Between Pulmonary Hypertension and Atrial Fibrillation: A Comprehensive Overview

by Danish Sultan, Bianca J. J. M. Brundel and Kondababu Kurakula

Cells 2025, 14(11), 839; https://doi.org/10.3390/cells14110839 - 4 Jun 2025

Viewed by 902

Abstract

Pulmonary hypertension (PH) is a progressive lung disease characterized by abnormal pulmonary vascular pressure and right ventricular (RV) dysfunction. Atrial arrhythmias, including atrial fibrillation (AF) and atrial flutter, are common in patients with PH and significantly contribute to disease progression and mortality. A [...] Read more.

Pulmonary hypertension (PH) is a progressive lung disease characterized by abnormal pulmonary vascular pressure and right ventricular (RV) dysfunction. Atrial arrhythmias, including atrial fibrillation (AF) and atrial flutter, are common in patients with PH and significantly contribute to disease progression and mortality. A bidirectional pathophysiological link exists between PH and AF, encompassing shared mechanisms such as endothelial dysfunction, DNA damage, autophagy, inflammation, and oxidative stress, as well as mutual risk factors, including diabetes, obesity, heart disease, and aging. Despite these shared pathways, limited research has been conducted to fully understand the intertwined relationship between PH and AF, hindering the development of effective treatments. In this review, we provide a comprehensive overview of the epidemiology of PH, the molecular mechanisms underlying the development of AF in PH, and the overlap in their pathophysiology. We also identify novel druggable targets and propose mechanism-based therapeutic approaches to treat this specific patient group. By shedding light on the molecular connection between PH and AF, this review aims to fuel the design and validation of innovative treatments to address this challenging comorbidity. Full article

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14 pages, 372 KiB

Open AccessArticle

Modified Methylation Following Electrostimulation in a Standardized Setting—Complementing a Transcriptomic Analysis

by Biagio Di Pietro, Simona Villata, Anna Plaksienko, Tiziana Guarnieri, Simeone Dal Monego, Margherita Degasperi, Pietro Di Lena, Danilo Licastro, Claudia Angelini, Francesca Frascella, Lucia Napione and Christine Nardini

Cells 2025, 14(11), 838; https://doi.org/10.3390/cells14110838 - 4 Jun 2025

Viewed by 371

Abstract

Electrical stimulation (ES) is widely employed in both clinical therapies and research settings where it has shown promise in promoting tissue regeneration, wound healing, and inflammation control. Research has also highlighted ES as a regulator of DNA demethylation, which plays a critical role [...] Read more.

Electrical stimulation (ES) is widely employed in both clinical therapies and research settings where it has shown promise in promoting tissue regeneration, wound healing, and inflammation control. Research has also highlighted ES as a regulator of DNA demethylation, which plays a critical role in nerve regeneration and cellular repair mechanisms. While the impact of ES on epigenetic processes is recognized, its broader effects on cellular functions, particularly in inflammation and wound healing, are less understood. We recently showed how ES impacts inflammatory states by modulating transcriptomic and metabolomic profiles in a 3Din vitromodel where human fibroblasts and keratinocytes are included in a collagen matrix, i.e., even in the absence of the nervous system. Here, we propose to deepen our exploration on the differential effects on DNA methylation, including an investigation of the correlation with age acceleration using a mitotic clock. These results confirm and caution on the differential effect of DC on inflamed and non-inflamed samples and suggest an involvement of direct current stimuli at 1 V (

D C 1

) in the control of senescent processes associated with mitosis and inflammation; the mechanistic details of these will have to be clarified with additional experiments. Full article

(This article belongs to the Special Issue The Epigenetic Landscape of Aging: Mechanisms and Impacts During Cellular and Organismal Longevity)

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21 pages, 3611 KiB

Open AccessArticle

A Pathophysiologically Hypertrophic 3T3-L1 Cell Model—An Alternative to Primary Cells Isolated from DIO Mice

by Isabell Kaczmarek, Kristiana Schüßler, Andreas Lindhorst, Martin Gericke and Doreen Thor

Cells 2025, 14(11), 837; https://doi.org/10.3390/cells14110837 - 3 Jun 2025

Viewed by 485

Abstract

Adipocyte hypertrophy in individuals with obesity is connected to alterations in adipocyte function. These pathophysiological changes are studied using animal models and adipose tissue engineering. However, knockdown, overexpression, and stimulation studies would benefit from an easily applicable cell model. Although several models (free [...] Read more.

Adipocyte hypertrophy in individuals with obesity is connected to alterations in adipocyte function. These pathophysiological changes are studied using animal models and adipose tissue engineering. However, knockdown, overexpression, and stimulation studies would benefit from an easily applicable cell model. Although several models (free fatty acids, glucose restriction, and long-term incubation) have previously been described, our evaluation demonstrated that they lack important features described for hypertrophic adipocytes found in obesity. Therefore, we aimed to develop a cell model depicting the pathophysiological state of adipocytes in obesity by applying novel approaches (insulin, macrophage supernatant, and Tnfα) using 3T3-L1 cells. To analyze changes in adipocyte phenotype and function, we detected the cell size, lipid accumulation, insulin sensitivity, cytokine/adipokine secretion, and expression of lipolytic enzymes. Combining long-term incubation with insulin and Tnfα co-stimulation, we found significantly increased cell size and lipid accumulation compared to 3T3-L1 adipocytes differentiated with standard protocols. Furthermore, these adipocytes showed significantly reduced insulin sensitivity, adiponectin secretion, and lipolytic enzyme expression, accompanied by increased IL6 and leptin secretion. In summary, the described cell model depicts pathophysiologically hypertrophic 3T3-L1 adipocytes. This model can be used for knockdown, overexpression, and stimulation studies, thereby serving as an alternative to primary cells isolated from DIO mice. Full article

(This article belongs to the Section Cellular Pathology)

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24 pages, 3076 KiB

Open AccessArticle

Strong Hsp90α/β Protein Expression in Advanced Primary CRC Indicates Short Survival and Predicts Response to the Hsp90α/β-Specific Inhibitor Pimitespib

by Sebastian B. M. Schmitz, Jakob Gülden, Marlene Niederreiter, Cassandra Eichner, Jens Werner and Barbara Mayer

Cells 2025, 14(11), 836; https://doi.org/10.3390/cells14110836 - 3 Jun 2025

Viewed by 529

Abstract

The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was [...] Read more.

The prognosis of advanced (UICC IIb-IV) primary colorectal cancer (pCRC) remains poor. More effective targeted therapies are needed. Heat shock protein 90 alpha/beta (Hsp90α/β) expression was immunohistologically quantified in 89 pCRCs and multivariately correlated with survival. Pimitespib (Pim, TAS-116), a Hsp90α/β-specific inhibitor, was tested in pCRC cell lines and patient-derived cancer spheroids (PDCS) and referenced to the pan-Hsp90 inhibitor ganetespib (Gan, STA-9090) and standard-of-care therapies. A total of 26.97% pCRCs showed strong tumoral Hsp90α/β expression (Hsp90α/β > 40%), which correlated with reduced PFS (HR: 3.785, 95%CI: 1.578–9.078, p = 0.003) and OS (HR: 3.502, 95%CI: 1.292–9.494, p = 0.014). Co-expression of Hsp90α/β > 40% with its clients BRAF-V600E and Her2/neu aggravated the prognosis (BRAF-V600E mutated: PFS, p = 0.002; OS, p = 0.012; Her2/neu score3: PFS, p = 0.029). The prognostic cut-off Hsp90α/β > 40% was also a predictor for response to Pim-based therapy. Pim efficacy was increased in combination with 5-FU, 5-FU + oxaliplatin, and 5-FU + irinotecan (all p < 0.001). Pim induced sensitization to all chemotherapies in HT-29 (p < 0.001), Caco-2 (p < 0.01), and HCT116 (p < 0.05) cells. Pim combined with encorafenib in HT-29 and with trastuzumab in Caco-2 cells was most effective in dual-target inhibition approaches (HT-29: p < 0.005; Caco-2: p < 0.05). The anti-cancer effect and chemosensitization of Pim-based therapy were prospectively confirmed in PDCS directly generated from Hsp90α/β > 40% pCRCs. Protein profiling combined with functional drug testing stratifies Hsp90α/β > 40% pCRC patients diagnosed with UICC IIb-IV for effective Pim-based therapy. Full article

(This article belongs to the Special Issue Heat Shock Proteins and Human Cancers)

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20 pages, 7340 KiB

Open AccessFeature PaperArticle

PTPA Governs Stress-Responsive Differentiation and Metabolic Homeostasis in Toxoplasma gondii

by Zhu Ying, Yuntong Wu, Yanqun Pei, Zheng Shang, Jing Liu and Qun Liu

Cells 2025, 14(11), 835; https://doi.org/10.3390/cells14110835 - 3 Jun 2025

Viewed by 375

Abstract

The protozoan parasite Toxoplasma gondii transitions between acute (tachyzoite) and chronic (bradyzoite) stages, enabling lifelong persistence in hosts. Iron depletion triggers bradyzoite differentiation, with the phosphotyrosyl phosphatase activator (PTPA) identified as a key regulator. Here, we define PTPA’s role in T. gondii pathogenesis. [...] Read more.

The protozoan parasite Toxoplasma gondii transitions between acute (tachyzoite) and chronic (bradyzoite) stages, enabling lifelong persistence in hosts. Iron depletion triggers bradyzoite differentiation, with the phosphotyrosyl phosphatase activator (PTPA) identified as a key regulator. Here, we define PTPA’s role in T. gondii pathogenesis. PTPA forms a ternary complex with PP2A A/C subunits, validated by reciprocal pull-down assays. Depleting PTPA impaired tachyzoite proliferation, invasion, and gliding motility, while stress-induced bradyzoites exhibited defective cyst formation and vacuolar swelling. Metabolic dysregulation included amylopectin accumulation and lipid droplet proliferation. The PP2A inhibitor LB-100 phenocopied PTPA depletion, suppressing tachyzoite growth and bradyzoite differentiation. TgPTPA emerges as a linchpin coordinating PP2A activity, metabolic flux, and lifecycle transitions. Its dual roles in acute virulence and chronic persistence, combined with LB-100’s efficacy, position the PTPA–PP2A axis as a promising target for antitoxoplasmosis strategies. Full article

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9 pages, 571 KiB

Open AccessPerspective

a-synuclein PET Imaging: From Clinical Utility in Multiple System Atrophy to the Possible Diagnosis of Parkinson’s Disease

by Francesca Capotosti

Cells 2025, 14(11), 834; https://doi.org/10.3390/cells14110834 - 3 Jun 2025

Viewed by 630

Abstract

The development of PET tracers for the detection of pathological alpha-synuclein (a-synuclein) has the potential to revolutionize the diagnosis, monitoring, and therapeutic interventions of synucleinopathies, including Parkinson’s disease. The journey toward identifying effective PET imaging agents, however, has faced significant challenges due to [...] Read more.

The development of PET tracers for the detection of pathological alpha-synuclein (a-synuclein) has the potential to revolutionize the diagnosis, monitoring, and therapeutic interventions of synucleinopathies, including Parkinson’s disease. The journey toward identifying effective PET imaging agents, however, has faced significant challenges due to the complexity and heterogeneity of the a-synuclein structures. Achieving the goal is further compounded by the low density of the pathological target, necessitating that the tracer exhibits a high binding potential, as well as the co-existence of other protein aggregates, requiring the tracer to be highly specific and selective for a-synuclein. In this perspective article, the challenges regarding developing PET tracers for a-synuclein are explored and summarized, together with the most significant recent advances in the field. These include the approaches used by our laboratories, leading to the publication of the first clinical PET images of a-synuclein pathology in patients with multiple system atrophy (MSA). Building on the current understanding of the different a-synuclein species and findings based on the success of PET tracers in the field of neurodegenerative diseases, future directions are considered also to achieve the imaging of a-synuclein pathology in Parkinson’s patients. Full article

(This article belongs to the Special Issue Development of PET Radiotracers for Imaging Alpha-Synuclein)

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24 pages, 6482 KiB

Open AccessArticle

Transmembrane Protein-184A Interacts with Syndecan-4 and Rab GTPases and Is Required to Maintain VE-Cadherin Levels

by Leanna M. Altenburg, Stephanie H. Wang, Grace O. Ciabattoni, Amelia Kennedy, Rachel L. O’Toole, Sara L. N. Farwell, M. Kathryn Iovine and Linda J. Lowe-Krentz

Cells 2025, 14(11), 833; https://doi.org/10.3390/cells14110833 - 3 Jun 2025

Viewed by 485

Abstract

VE-cadherin (VE-cad) membrane stability and localization regulates adhesion formation and actin cytoskeleton dynamics in angiogenesis and vascular remodeling and requires the heparan sulfate proteoglycan (HSPG), Syndecan-4 (Sdc4). This study characterizes the interactions of the heparin receptor, Transmembrane protein-184A (TMEM184A), and Sdc4 in bovine [...] Read more.

VE-cadherin (VE-cad) membrane stability and localization regulates adhesion formation and actin cytoskeleton dynamics in angiogenesis and vascular remodeling and requires the heparan sulfate proteoglycan (HSPG), Syndecan-4 (Sdc4). This study characterizes the interactions of the heparin receptor, Transmembrane protein-184A (TMEM184A), and Sdc4 in bovine aortic endothelial cells (BAOECs) and the regenerating Zebrafish (ZF) caudal fin and measures the effect of siRNA TMEM184A KD (siTMEM) and TMEM184A overexpression (TMEM OE) on VE-cad levels and localization in confluent and sub-confluent cultured BAOECs. Additionally, we examined the effect of siTMEM on key Rab GTPase trafficking regulators and migrating BAOECs in scratch wound healing assays. We demonstrated that TMEM184A and Sdc4 colocalize in BAOECs and that Sdc4 OE increases colocalization in an HS chain dependent manner, while both Tmem184a and Sdc4 cooperate synergistically in ZF fin angiogenic and tissue repair. We also showed that siTMEM decreases VE-cad membrane and cytoplasmic levels, while increasing scratch wound migration rates. However, TMEM OE cells show increased vesicle formation and VE-cad trafficking and membrane recovery. These findings characterize TMEM184A-Sdc4 cooperation in angiogenesis and indicate a dual function of TMEM184A in signaling and trafficking in vascular cells that promotes VE-cad recovery and membrane localization. Full article

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24 pages, 7622 KiB

Open AccessArticle

Hypoxia Promotes the In Vitro Proliferation of Buffalo Spermatogonial Cells by Increasing Lactate and H3K18la Lactylation Levels

by Mengqi Li, Yanyu Ma, Shenzhi Wang, Haiying Zheng, Chunyan Yang, Anqin Duan, Benliang Zhou, Jianghua Shang, Xingwei Liang and Xiaogan Yang

Cells 2025, 14(11), 832; https://doi.org/10.3390/cells14110832 - 3 Jun 2025

Viewed by 494

Abstract

Hypoxia benefits the proliferation and maintenance of animal spermatogonial cells; however, the underlying mechanism remains incompletely understood. This study aims to investigate the role and mechanism of the hypoxia–glycolysis–histone lactylation axis in the proliferation of buffalo spermatogonial cells (bSCs). bSCs were cultured under [...] Read more.

Hypoxia benefits the proliferation and maintenance of animal spermatogonial cells; however, the underlying mechanism remains incompletely understood. This study aims to investigate the role and mechanism of the hypoxia–glycolysis–histone lactylation axis in the proliferation of buffalo spermatogonial cells (bSCs). bSCs were cultured under different oxygen concentrations to observe changes in cell proliferation. RNA-seq was used to analyze gene expression and signaling pathways. Changes in lactylation were monitored, and CUT&Tag-seq was utilized to determine the regulatory effects of lactylation on gene expression. The glycolytic pathway was regulated to validate the results of the bioinformatic analysis. Oxygen concentrations between 2.5% and 10% support the proliferation of bSCs, with 5% having the most pronounced effect. An amount of 5% oxygen significantly increased the proliferation and pluripotency of bSCs while also promoting glycolysis and lactylation. Inhibition of glycolysis eliminated the proliferative effects of hypoxia. By analyzing genes associated with the key lactylation site H3K18la using CUT&Tag technology, we found that it is closely linked to genes involved in the regulation of proliferation. After inhibition of HK-2 expression, cell proliferation, H3K18la expression, and the expression of these target genes were all suppressed. Hypoxia promotes the proliferation of bSCs via activation of glycolysis, leading to an increase in H3K18la and altered expression of its target genes. Full article

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19 pages, 3237 KiB

Open AccessArticle

Modulation of ER Stress and Inflammation by S-Ketamine, R-Ketamine, and Their Metabolites in Human Microglial Cells: Insights into Novel Targets for Depression Therapy

by Marta Jóźwiak-Bębenista, Anna Wiktorowska-Owczarek, Małgorzata Siatkowska, Piotr Komorowski, Aneta Włodarczyk, Edward Kowalczyk and Paulina Sokołowska

Cells 2025, 14(11), 831; https://doi.org/10.3390/cells14110831 - 3 Jun 2025

Viewed by 475

Abstract

Despite affecting millions worldwide, major depressive disorder (MDD) remains a therapeutic challenge, with approximately one-third of patients failing to respond to standard treatments. The need for innovative, molecularly driven therapies has turned attention to ketamine and its enantiomers. While S-ketamine is clinically approved [...] Read more.

Despite affecting millions worldwide, major depressive disorder (MDD) remains a therapeutic challenge, with approximately one-third of patients failing to respond to standard treatments. The need for innovative, molecularly driven therapies has turned attention to ketamine and its enantiomers. While S-ketamine is clinically approved for treatment-resistant depression (TRD), it has various psychoactive side effects and potential for abuse. Hence, it is necessary to identify alternative compounds, such as R-ketamine, and their metabolites (e.g., 2S,6S-hydroxynorketamine and 2R,6R-hydroxynorketamine, collectively referred to as HNKs). Emerging evidence suggests that the pathophysiology of MDD involves two processes regulated by the unfolded protein response (UPR): endoplasmic reticulum (ER) stress and neuroinflammation. As such, they represent promising therapeutic targets. The study provides the first direct comparison of ketamine enantiomers and their metabolites in modulating ER stress and inflammatory signaling in human microglial cells (HMC3), which play key roles in neuroimmune communication. Both S-ketamine and R-ketamine, along with their metabolites, significantly reduced both the expression and protein levels of CHOP and GRP78—two critical UPR components—under tunicamycin-induced ER stress conditions. Additionally, the compounds significantly decreased IL-6 levels and, to a lesser extent, IL-8 levels in lipopolysaccharide (LPS)-stimulated microglia, indicating anti-inflammatory potential. Taken together, these findings highlight a novel glia-targeted mechanism by which ketamine and its metabolites modulate ER stress and neuroinflammation. CHOP and GRP78 appear to be stress-responsive molecular markers within the UPR pathway. These results justify further in vivo validation and support the development of antidepressants with fewer psychoactive effects. Full article

(This article belongs to the Section Cells of the Nervous System)

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13 pages, 3930 KiB

Open AccessArticle

Isolation and Characterization of Articular Cartilage-Derived Cells Obtained by Arthroscopic Cartilage Biopsy from Non-Osteoarthritic Patients

by Pedro Nogueira Giglio, Débora Levy, Phelipe Oliveira Favaron, Lucas da Ponte Melo, Cadiele Oliana Reichert, Fábio Alessandro de Freitas, Juliana Sampaio Silva, Walcy Paganelli Rosolia Teodoro, Sérgio Paulo Bydlowski and Marco Kawamura Demange

Cells 2025, 14(11), 830; https://doi.org/10.3390/cells14110830 - 3 Jun 2025

Viewed by 372

Abstract

Cartilage-derived migratory cells show great potential for autologous use in cartilage repair surgery. However, their collection through arthroscopic biopsy has not been previously reported in individuals without osteoarthritis. This study aimed to characterize migratory cartilage cells isolated from arthroscopic biopsies of volunteers without [...] Read more.

Cartilage-derived migratory cells show great potential for autologous use in cartilage repair surgery. However, their collection through arthroscopic biopsy has not been previously reported in individuals without osteoarthritis. This study aimed to characterize migratory cartilage cells isolated from arthroscopic biopsies of volunteers without osteoarthritis and compare them with cells obtained by enzymatic digestion. Cell cultures were successfully established using both methods—enzymatic digestion and cell migration—from cartilage explants, with no significant differences observed in stem cell markers or plasticity between the cell lines. Cells derived from both procedures exhibited characteristics of mesenchymal stem cell, including fibroblast-like morphology, expression of CD29, CD90, and CD105 markers, absence of hematopoietic and endothelial cell markers, and the ability to differentiate into adipocytes, chondrocytes, and osteoblasts under appropriate conditions. Cells obtained by migration showed lower expression of collagen I and II, along with reduce collagen II/collagen I ratio, both positively associated with chondral matrix production, as well as lower RUNX2 expression. However, no differences were found in the levels of SOX9, essential for chondrogenic differentiation, or in the expression of perlecan gene. Syndecan-1 expression was lower in cells obtained by migration. In conclusion, this study demonstrates that cartilage-derived migratory cells can be successfully obtained from arthroscopic biopsies of individuals without osteoarthritis, presenting comparable dedifferentiation and plasticity profiles. Furthermore, these cells express essential chondrogenic markers and proteins. Although further in vivo studies are needed to determine their effective regenerative potential, cartilage-derived migratory cells represent a promising avenue for cartilage repair strategies. Full article

(This article belongs to the Special Issue Advances in Cell-Based Studies and Therapeutic Approaches for Tissue Regeneration)

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26 pages, 2167 KiB

Open AccessReview

Endometrial Organoids and Their Role in Modeling Human Infertility

by Abdullah Jabri, Mohamed Alsharif, Tasnim Abbad, Bader Taftafa, Abdulaziz Mhannayeh, Abdulrahman Elsalti, Fayrouz Attia, Tanveer Ahmad Mir, Islam Saadeldin and Ahmed Yaqinuddin

Cells 2025, 14(11), 829; https://doi.org/10.3390/cells14110829 - 3 Jun 2025

Viewed by 583

Abstract

Endometrial organoids (EOs) have emerged as a powerful three-dimensional (3D) model for studying the human endometrium, offering new insights into infertility and reproductive disorders. These self-organizing miniature structures closely mimic the cellular composition, hormonal responsiveness, and functional characteristics of the endometrium, making them [...] Read more.

Endometrial organoids (EOs) have emerged as a powerful three-dimensional (3D) model for studying the human endometrium, offering new insights into infertility and reproductive disorders. These self-organizing miniature structures closely mimic the cellular composition, hormonal responsiveness, and functional characteristics of the endometrium, making them valuable preclinical tools for investigating implantation failure, endometrial receptivity, and disease pathophysiology. This review explores the role of EOs in reproductive medicine, with a focus on their applications in infertility research, environmental toxicology, and regenerative therapies. Traditional 2D cell cultures fail to capture the complexity of these physiological and pathological interactions, whereas organoids provide a physiologically relevant system for studying implantation mechanisms. Additionally, co-culture models incorporating stromal and immune cells have further enhanced our understanding of the maternal–fetal interface. Beyond modeling infertility, EOs hold significant promise for therapeutic applications. Advances in organoid transplantation have demonstrated potential for treating endometrial dysfunction-related infertility, including conditions such as Asherman’s syndrome and thin endometrium. Moreover, these models serve as a platform for drug screening and biomarker discovery, paving the way for personalized reproductive medicine. Despite their transformative potential, limitations remain, including the need for improved extracellular matrices, vascularization, and immune system integration. This review emphasizes the significant contributions of EOs to the field of infertility treatment and reproductive biology by examining recent advancements and emerging research. The continued refinement of these models would offer a paradigm for improving assisted reproductive technologies (ARTs) and regenerative medicine outcomes, offering new hope for individuals facing infertility challenges. Full article

(This article belongs to the Special Issue Organoids and Models from Stem Cells)

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23 pages, 6264 KiB

Open AccessArticle

Prognostic Significance of Macrophage Phenotypes in Peri-Tumoral Normal Tissue of Early-Stage Breast Cancer

by Marcel Hirschmann, Sören Schnellhardt, Matthias Rübner, Sarah Segelhorst, Oliver Ott, Ramona Erber, Christoph Daniel, Maike Büttner-Herold, Paul Gass, Rainer Fietkau and Luitpold Distel

Cells 2025, 14(11), 828; https://doi.org/10.3390/cells14110828 - 3 Jun 2025

Viewed by 386

Abstract

In recent years, tumor-infiltrating inflammatory cells within the tumor microenvironment have been extensively studied. However, much less is known about inflammatory cells in the normal tissue surrounding tumors. In this study, we assess the prognostic significance of tumor-associated macrophages (TAMs) in relation to [...] Read more.

In recent years, tumor-infiltrating inflammatory cells within the tumor microenvironment have been extensively studied. However, much less is known about inflammatory cells in the normal tissue surrounding tumors. In this study, we assess the prognostic significance of tumor-associated macrophages (TAMs) in relation to disease-free survival (DFS) in patients with early-stage breast cancer. Our cohorts included patients from the APBI and BBCC trials, with eligible tumors being small in size and showing no signs of metastasis. We analyzed eight distinct inflammatory cell types in the normal tissue surrounding tumors, with a particular focus on the various macrophage subsets. There were clear differences in the frequencies of the different inflammatory cells, with a higher abundance of cells being found in the intraepithelial compartment compared to the stromal compartment. Notably, we found that M2-type macrophages located in the stromal compartment of tumor distant normal tissue exhibited a positive prognostic impact, in contrast to the M2-type macrophages found within the tumor itself. In the normal tissue surrounding tumors, there are surprisingly clear prognostic predictions for DFS. Normal tissue surrounding breast cancer tumors is clearly influenced by the tumor and could also influence the tumor in terms of growth and metastasis. Tumor-influenced inflammatory cells in the surrounding normal tissue could prevent the immune system from acting against the tumor and promote tumor growth through inflammation. Full article

(This article belongs to the Special Issue Biomarkers in Breast Cancer)

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21 pages, 4654 KiB

Open AccessArticle

Air-Exposure- and Reoxygenation-Stimulated Expressions of Caspase-3 and Induction of Apoptosis in the Central Nervous System of the Crab Erimacrus isenbeckii

by Elena Kotsyuba and Vyacheslav Dyachuk

Cells 2025, 14(11), 827; https://doi.org/10.3390/cells14110827 - 2 Jun 2025

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Abstract

Air exposure stress during live transport and subsequent reoxygenation are factors in the development of molecular/pathological and compensatory/adaptive responses. They affect the physiological functions and survival of economically important invertebrate species, in particular, crustaceans. In this study, we consider the effects of anoxia [...] Read more.

Air exposure stress during live transport and subsequent reoxygenation are factors in the development of molecular/pathological and compensatory/adaptive responses. They affect the physiological functions and survival of economically important invertebrate species, in particular, crustaceans. In this study, we consider the effects of anoxia and subsequent reoxygenation on the physiological responses, signaling pathways involved in stress, and cell apoptosis in the central nervous system (CNS) of the horsehair crab, Erimacrus isenbeckii. The results showed that 1 day of air exposure stress and 1 subsequent day of reoxygenation cause the immunoreactivity of tyrosine hydroxylase (TH) and neuropeptide Y (NPY) to change, suggesting that these changes may be associated with adaptive responses, which are presumably employed to avoid oxidative damage and provide the initial mechanism for survival. Caspase-3 immunoreactive neurons increased eight-fold in the brain and 7.2-fold in the VNC after 1 day of reoxygenation, and the TUNEL-positive cell percentage rose from 0% (control) to 8.4% in the brain and from 1.7% (control) to 13% in the VNC. The results of our study provide evidence that anoxia and reoxygenation can activate caspase-3 and facilitate apoptosis in the CNS of crabs. These results provide evidence that even short-term air exposure stress followed by reoxygenation can trigger significant apoptotic cell death in crustacean neural tissue, which is important for developing better live transport practices. Full article

(This article belongs to the Section Cell Proliferation and Division)

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22 pages, 3926 KiB

Open AccessFeature PaperArticle

Avenanthramide-C as Alzheimer’s Disease-Modifying Therapy: Early and Sustained Intervention Prevents Disease Progression in Mouse Models

by Alen Benhur Pravin Nathan, Areeba Aziz, Semyeong Choi, Seunghee Lee, Seyoung Jeon, Hyung-Seok Kim, Jonghyun Cho and Jihoon Jo

Cells 2025, 14(11), 826; https://doi.org/10.3390/cells14110826 - 2 Jun 2025

Viewed by 511

Abstract

Most approved drugs for Alzheimer’s disease (AD) are indicated for early to moderate stages and primarily target amyloid-beta or neurotransmitter systems. While these treatments may slow cognitive decline, they do not halt disease progression and are often limited by high cost and modest [...] Read more.

Most approved drugs for Alzheimer’s disease (AD) are indicated for early to moderate stages and primarily target amyloid-beta or neurotransmitter systems. While these treatments may slow cognitive decline, they do not halt disease progression and are often limited by high cost and modest efficacy. Natural compounds are increasingly being explored as alternative interventions. Our previous study showed that oral administration of Avenanthramide-C (Avn-C), a natural polyphenol from oats, for 14 days from early AD stages improved cognition and reduced neuroinflammation in AD mice. To assess its long-term potential, in this study we extended Avn-C treatment to three months starting from early disease stages in 5xFAD and Tg2576 models. Sustained administration preserved recovered long-term potentiation (LTP) by maintaining AMPK activation and inhibiting caspase-3 and GSK3β, thereby reducing amyloid accumulation and tau hyperphosphorylation in the hippocampus. Avn-C also maintained anti-inflammatory effects by suppressing NF-κB-mediated proinflammatory cytokine release and preventing chronic microglial activation. This promoted microglial coverage of plaques in vivo and enhanced phagocytosis in vitro. Our findings suggest that early and sustained Avn-C treatment preserves cognitive function, modulates multiple pathological pathways, and may slow or prevent AD progression by targeting early neurodegenerative processes before irreversible damage occurs. Full article

(This article belongs to the Special Issue Natural Products in Neurodegenerative Diseases: Current Trends and Future Perspectives)

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26 pages, 2663 KiB

Open AccessReview

Innate Lymphoid Cells in Inflammatory Bowel Disease

by Xin Yao, Kaiming Ma, Yangzhuangzhuang Zhu and Siyan Cao

Cells 2025, 14(11), 825; https://doi.org/10.3390/cells14110825 - 2 Jun 2025

Viewed by 435

Abstract

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract with rising incidence and an unclear etiology. Innate lymphoid cells (ILCs) have recently emerged as key regulators of mucosal immunity and tissue homeostasis and [...] Read more.

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract with rising incidence and an unclear etiology. Innate lymphoid cells (ILCs) have recently emerged as key regulators of mucosal immunity and tissue homeostasis and are increasingly implicated in IBD. Unlike adaptive lymphocytes, ILCs do not require antigen recognition and clonal expansion to respond rapidly to environmental cues and shape immune responses. In a healthy gut, ILCs maintain intestinal homeostasis by guarding the epithelial barrier, protecting against pathogens, and mounting proper responses to external insults. However, their altered differentiation, proliferation, recruitment, activation, and interaction with other host cells, microbiota, and environmental stimuli may contribute to IBD. In this review, we discuss recent advances in understanding murine and human ILCs in the context of intestinal inflammation and IBD. A deeper understanding of ILC-mediated immune mechanisms may offer novel therapeutic strategies for restoring intestinal homeostasis and improving personalized management of IBD. Full article

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24 pages, 8383 KiB

Open AccessArticle

Idebenone Mitigates Traumatic-Brain-Injury-Triggered Gene Expression Changes to Ephrin-A and Dopamine Signaling Pathways While Increasing Microglial Genes

by Hyehyun Hwang, Chinmoy Sarkar, Boris Piskoun, Naibo Zhang, Apurva Borcar, Courtney L. Robertson, Marta M. Lipinski, Nagendra Yadava, Molly J. Goodfellow and Brian M. Polster

Cells 2025, 14(11), 824; https://doi.org/10.3390/cells14110824 - 1 Jun 2025

Viewed by 474

Abstract

Traumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology Panel to [...] Read more.

Traumatic brain injury (TBI) leads to persistent pro-inflammatory microglial activation implicated in neurodegeneration. Idebenone, a coenzyme Q10 analogue that interacts with both mitochondria and the tyrosine kinase adaptor SHC1, inhibits aspects of microglial activation in vitro. We used the NanoString Neuropathology Panel to test the hypothesis that idebenone post-treatment mitigates TBI-pathology-associated acute gene expression changes by moderating the pro-inflammatory microglial response to injury. Controlled cortical impact to adult male mice increased the microglial activation signature in the peri-lesional cortex at 24 h post-TBI. Unexpectedly, several microglial signature genes upregulated by TBI were further increased by post-injury idebenone administration. However, idebenone significantly attenuated TBI-mediated perturbations to gene expression associated with behavior, particularly in the gene ontology–biological process (GO:BP) pathways “ephrin receptor signaling” and “dopamine metabolic process”. Gene co-expression analysis correlated levels of microglial complement component 1q (C1q) and the neurotrophin receptor gene Ntrk1 to large (>3-fold) TBI-induced decreases in dopamine receptor genes Drd1 and Drd2 that were mitigated by idebenone treatment. Bioinformatics analysis identified SUZ12 as a candidate transcriptional regulator of idebenone-modified gene expression changes. Overall, the results suggest that idebenone may enhance TBI-induced microglial number within the first 24 h of TBI and identify ephrin-A and dopamine signaling as novel idebenone targets. Full article

(This article belongs to the Special Issue Mitochondrial Dysfunction in Neurodegeneration: A Translational Perspective)

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21 pages, 1835 KiB

Open AccessReview

Distinct Types of Regulated Cell Death in Melanoma

by Qi Wu, Shuang Liang, Guo-Jun Shi, Guo-Liang Meng and Sheng-Ju Yang

Cells 2025, 14(11), 823; https://doi.org/10.3390/cells14110823 - 1 Jun 2025

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Abstract

Resistance to cell death is one of the core hallmarks of cancer, with regulatory abnormalities particularly pronounced in the malignant progression and therapeutic resistance of melanoma. This review aims to systematically summarize the roles and mechanisms of regulated cell death (RCD) in melanoma. [...] Read more.

Resistance to cell death is one of the core hallmarks of cancer, with regulatory abnormalities particularly pronounced in the malignant progression and therapeutic resistance of melanoma. This review aims to systematically summarize the roles and mechanisms of regulated cell death (RCD) in melanoma. Currently, distinct types of RCD, including apoptosis, autophagy, pyroptosis, immunogenic cell death, necroptosis, and ferroptosis, have all been found to be involved in melanoma. Autophagy promotes the survival of melanoma cells under stress conditions through metabolic adaptation, yet its excessive activation can trigger cell death. Immunogenic cell death has the capacity to elicit adaptive immune responses in immunocompetent syngeneic hosts. Necroptosis, governed by the receptor-interacting protein kinase 1 (RIPK1)/RIPK3 mixed lineage kinase domain-like protein (MLKL) signaling axis, can synergize with immunotherapy to enhance anti-melanoma immune responses when activated. Pyroptosis, mediated by Gasdermin proteins, induces the release of inflammatory factors that reshape the tumor microenvironment and enhance the efficacy of immune checkpoint inhibitors. Ferroptosis, characterized by lipid peroxidation, can overcome melanoma resistance by targeting the solute carrier family 7 member 11 (SLC7A11)/glutathione peroxidase 4 (GPX4) axis. Therapeutic strategies targeting RCD pathways have demonstrated breakthrough potential. Several agents have been developed to target RCD in order to suppress melanoma. Full article

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