Cells

12 pages, 2505 KiB

Open AccessArticle

The Expression of Shmt Genes in Amphioxus Suggests a Role in Tissue Proliferation Rather than in Neurotransmission

by Matteo Bozzo, Emanuele Serafini, Giacomo Rosa, Virginia Bazzurro, Andrea Amaroli, Sara Ferrando, Michael Schubert and Simona Candiani

Cells 2025, 14(14), 1071; https://doi.org/10.3390/cells14141071 (registering DOI) - 13 Jul 2025

Abstract

Serine hydroxymethyltransferases (SHMTs) are key enzymes in one-carbon metabolism, with vertebrates possessing two paralogs, cytosolic SHMT1 and mitochondrial SHMT2, implicated in nucleotide biosynthesis and glycine metabolism. In this study, we investigate the evolutionary history of animal Shmt genes and analyze the expression patterns [...] Read more.

Serine hydroxymethyltransferases (SHMTs) are key enzymes in one-carbon metabolism, with vertebrates possessing two paralogs, cytosolic SHMT1 and mitochondrial SHMT2, implicated in nucleotide biosynthesis and glycine metabolism. In this study, we investigate the evolutionary history of animal Shmt genes and analyze the expression patterns of Shmt genes in developing amphioxus (Branchiostoma lanceolatum). Phylogenetic analyses indicate the presence of Shmt1 and Shmt2 orthologs in deuterostomes, spiralians and placozoans, which is consistent with an ancient Shmt gene duplication event predating bilaterian diversification. Gene expression analyses in developing amphioxus show that Shmt2 expression is confined to the somites and absent from neural tissues. In contrast, Shmt1 is broadly expressed across germ layers, but its transcription is restricted to tissues characterized by strong cell proliferation. Notably, Shmt1 expression in the nervous system does not match the distribution of glycinergic neuron populations, implying a negligible role in glycine neurotransmitter synthesis. Instead, the spatial correlation of Shmt1 expression with mitotically active domains suggests a primary function in nucleotide biosynthesis via one-carbon metabolism. These findings indicate that SHMTs predominantly support cell proliferation rather than neurotransmission in amphioxus. Full article

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

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17 pages, 6342 KiB

Open AccessArticle

Regulation of Hindbrain Vascular Development by rps20 in Zebrafish

by Xinyu Shen, Zhaozhi Wen, Shunze Deng, Yuxuan Qiu, Weijie Ma, Xinyue Dong, Jie Gong, Yu Zhang, Dong Liu and Bing Xu

Cells 2025, 14(14), 1070; https://doi.org/10.3390/cells14141070 (registering DOI) - 13 Jul 2025

Abstract

During aging, the brain vasculature undergoes significant deterioration characterized by increased arterial tortuosity, compromised blood–brain barrier integrity, and reduced cerebral blood flow, all of which contribute to various neurological disorders. Thus, understanding the mechanisms underlying aging-related cerebrovascular defects is critical for developing strategies [...] Read more.

During aging, the brain vasculature undergoes significant deterioration characterized by increased arterial tortuosity, compromised blood–brain barrier integrity, and reduced cerebral blood flow, all of which contribute to various neurological disorders. Thus, understanding the mechanisms underlying aging-related cerebrovascular defects is critical for developing strategies to alleviate aging-associated neurological diseases. In this study, we investigated the role of aging-related genes in brain vascular development using zebrafish as an in vivo model. By thoroughly analyzing scRNA-seq datasets of mid- and old-aged brain vascular endothelial cells (human/mouse), we found ribosomal protein S20 (rps20) significantly down-regulated during aging. qPCR analysis and whole-mount in situ hybridization validated a high expression of rps20 during early zebrafish development, which progressively decreased in adult and aged zebrafish brains. Functional studies using the CRISPR/Cas9-mediated knockout of rps20 revealed an impaired growth of central arteries in the hindbrain and a marked increased intracranial hemorrhage incidence. Mechanistically, qPCR analysis demonstrated a significant downregulation of vegfa, cxcl12b, and cxcr4a, key signaling molecules required for hindbrain vascular development, in rps20-deficient embryos. In conclusion, our findings demonstrate that rps20 is essential for proper brain vascular development and the maintenance of vascular homeostasis in zebrafish, revealing a novel mechanism by which aging-related genes regulate brain vascular development. This study provides new insights that may aid in understanding and treating aging-associated vascular malformations and neurological pathologies. Full article

(This article belongs to the Special Issue Decoding the Complexity of Angiogenesis: Insights into Vascular Formation and Disease)

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16 pages, 520 KiB

Open AccessReview

Alzheimer’s Disease–Thrombosis Comorbidity: A Growing Body of Evidence from Patients and Animal Models

by Joanna Koch-Paszkowski, Christopher Sennett and Giordano Pula

Cells 2025, 14(14), 1069; https://doi.org/10.3390/cells14141069 (registering DOI) - 12 Jul 2025

Abstract

Background/Objectives: A growing body of evidence is amassing in the literature suggesting a correlation between Alzheimer’s disease (AD) and thrombotic vascular complications, which led to the suggestive hypothesis that thrombosis may contribute to AD onset and progression by damaging the neurovasculature and reducing [...] Read more.

Background/Objectives: A growing body of evidence is amassing in the literature suggesting a correlation between Alzheimer’s disease (AD) and thrombotic vascular complications, which led to the suggestive hypothesis that thrombosis may contribute to AD onset and progression by damaging the neurovasculature and reducing the cerebral blood flow. In turn, low cerebral blood flow is likely to contribute to neurodegeneration by reducing nutrient and oxygen supply and impairing toxic metabolite removal from the brain tissue. Methods: We searched the literature for studies in animal models of AD or patients diagnosed with the disease that reported circulating markers of platelet hyperactivity or hypercoagulation, or histological evidence of brain vascular thrombosis. Results: Platelet hyperactivity and hypercoagulability have been described in multiple animal models of AD, and histological evidence of neurovascular thrombosis has also been reported. Similarly, clinical studies on patients with AD showed circulating markers of platelet hyperactivity and hypercoagulation, or histological evidence of neurovascular thrombosis collected from post-mortem brain tissue samples. Conclusions: Taken together, a convincing picture is emerging that suggests a strong correlation between systemic or neurovascular thrombosis and AD. Nonetheless, a mechanistic role for haemostasis dysregulation and neurovascular damage in the onset or the progression of AD remains to be proven. Future research should focus on this important question in order to clarify the mechanisms underlying AD and identify a treatment for this disease. Full article

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14 pages, 1377 KiB

Open AccessArticle

miR-302a/b/d-3p Differentially Expressed During Frontonasal Development Is Sensitive to Retinoic Acid Exposure

by Chihiro Iwaya, Akiko Suzuki, Goo Jun and Junichi Iwata

Cells 2025, 14(14), 1068; https://doi.org/10.3390/cells14141068 - 11 Jul 2025

Abstract

Any failure in frontonasal development can lead to malformations at the middle facial region, such as frontonasal dysplasia, midfacial clefts, and hyper/hypotelorism. Various environmental factors influence morphogenesis through epigenetic regulations, including the action of noncoding microRNAs (miRNAs). However, it remains unclear how miRNAs [...] Read more.

Any failure in frontonasal development can lead to malformations at the middle facial region, such as frontonasal dysplasia, midfacial clefts, and hyper/hypotelorism. Various environmental factors influence morphogenesis through epigenetic regulations, including the action of noncoding microRNAs (miRNAs). However, it remains unclear how miRNAs are involved in the frontonasal development. In our analysis of publicly available miRNA-seq and RNA-seq datasets, we found that miR-28a-5p, miR-302a-3p, miR-302b-3p, and miR-302d-3p were differentially expressed in the frontonasal process during embryonic days 10.5 to 13.5 (E10.5–E13.5) in mice. Overexpression of these miRNAs led to a suppression of cell proliferation in cultured mouse embryonic frontonasal mesenchymal (MEFM) cells as well as in O9-1 cells, a cranial neural crest cell line. Through advanced bioinformatic analyses and miRNA-gene regulation assays, we identified that miR-28a-5p regulated a total of 25 genes, miR-302a-3p regulated 23 genes, miR-302b-3p regulated 22 genes, and miR-302d-3p regulated 20 genes. Notably, the expression of miR-302a/b/d-3p—unlike miR-28a-5p—was significantly upregulated by excessive exposure to all-trans retinoic acid (atRA) that induces craniofacial malformations. Inhibition of these miRNAs restored the reduced cell proliferation caused by atRA by normalizing the expression of target genes associated with frontonasal anomalies. Therefore, our findings suggest that miR-302a/b/d-3p plays a crucial role in the development of frontonasal malformations. Full article

(This article belongs to the Special Issue The Silent Regulators: Non-Coding RNAs in Cell Function and Disease)

22 pages, 2521 KiB

Open AccessArticle

Assessment of Feasibility of the M2 Macrophage-Based Adoptive Gene Transfer Strategy for Osteoarthritis with a Mouse Model

by Matilda H.-C. Sheng, David J. Baylink, Charles H. Rundle and Kin-Hing William Lau

Cells 2025, 14(14), 1067; https://doi.org/10.3390/cells14141067 - 11 Jul 2025

Abstract

Current osteoarthritis (OA) therapies fail to yield long-term clinical benefits, due in part to the lack of a mechanism for the targeted and confined delivery of therapeutics to OA joints. This study evaluates if M2 macrophages are effective cell vehicles for the targeted [...] Read more.

Current osteoarthritis (OA) therapies fail to yield long-term clinical benefits, due in part to the lack of a mechanism for the targeted and confined delivery of therapeutics to OA joints. This study evaluates if M2 macrophages are effective cell vehicles for the targeted and confined delivery of therapeutic genes to OA joints. CT bioluminescence in vivo cell tracing and fluorescent microscopy reveal that intraarticularly injected M2 macrophages were recruited to and retained at inflamed synovia. The feasibility of an M2 macrophage-based adoptive gene transfer strategy for OA was assessed using IL-1Ra as the therapeutic gene in a mouse tibial plateau injury model. Mouse M2 macrophages were transduced with lentiviral vectors expressing IL-1Ra or GFP. The transduced macrophages were intraarticularly injected into injured joints at 7 days post-injury and OA progression was monitored with plasma COMP and histology at 4 weeks. The IL-1Ra-expressing M2 macrophage treatment reduced plasma COMP, increased the area and width of the articular cartilage layer, decreased synovium thickness, and reduced the OARSI OA score without affecting the osteophyte maturity and meniscus scores when compared to the GFP-expressing M2 macrophage-treated or PBS-treated controls. When the treatment was given at 5 weeks post-injury, at which time OA should have developed, the IL-1Ra-M2 macrophage treatment also reduced plasma COMP, had a greater articular cartilage area and width, decreased synovial thickness, and reduced the OARSI OA score without an effect on the meniscus and osteophyte maturity scores at 8 weeks post-injury. In conclusion, the IL-1Ra-M2 macrophage treatment, given before or after OA was developed, delayed OA progression, indicating that the M2 macrophage-based adoptive gene transfer strategy for OA is tenable. Full article

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

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32 pages, 1368 KiB

Open AccessReview

Calcium Unified: Understanding How Calcium’s Atomic Properties Impact Human Health

by Karen B. Kirkness, John Sharkey and Suzanne Scarlata

Cells 2025, 14(14), 1066; https://doi.org/10.3390/cells14141066 - 11 Jul 2025

Abstract

Calcium plays a major role in all cellular functions, and its regulation is important in all aspects of human health. This key role calcium plays in cell function can be traced to its unique molecular coordination geometry, which is often overlooked in understanding [...] Read more.

Calcium plays a major role in all cellular functions, and its regulation is important in all aspects of human health. This key role calcium plays in cell function can be traced to its unique molecular coordination geometry, which is often overlooked in understanding calcium function. In this review, we integrate calcium’s ability to form various complexes with proteins and small molecules with its role as a key signaling atom. We argue that calcium’s ability to vary its coordination structures, compared to magnesium’s rigid geometry, explains its importance in biological functions. By examining calcium-mediated proteins, such as those containing EF-hand domains and those that assemble and stabilize the extracellular matrix in tissue organization, we demonstrate how calcium’s varied geometric coordination serves as both a signaling molecule and a regulator of physiological homeostasis. Full article

(This article belongs to the Section Cell Microenvironment)

21 pages, 4829 KiB

Open AccessArticle

Temporal and Severity-Dependent Alterations in Plasma Extracellular Vesicle Profiles Following Spinal Cord Injury

by Jamie Cooper, Scott Tait Airey, Eric Patino, Theo Andriot, Mousumi Ghosh and Damien D. Pearse

Cells 2025, 14(14), 1065; https://doi.org/10.3390/cells14141065 - 11 Jul 2025

Abstract

Spinal cord injury (SCI) triggers both local and systemic pathological responses that evolve over time and differ with injury severity. Small extracellular vesicles (sEVs), known mediators of intercellular communication, may serve as biomarkers reflecting these complex dynamics. In this study, we investigated whether [...] Read more.

Spinal cord injury (SCI) triggers both local and systemic pathological responses that evolve over time and differ with injury severity. Small extracellular vesicles (sEVs), known mediators of intercellular communication, may serve as biomarkers reflecting these complex dynamics. In this study, we investigated whether SCI severity modulates the composition and abundance of circulating plasma-derived sEVs across subacute and chronic phases. Using a graded thoracic contusion model in mice, plasma was collected at defined timepoints post-injury. sEVs were isolated via size-exclusion chromatography and characterized using nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and MACSPlex surface marker profiling. We observed an SCI-dependent increase in sEVs during the subacute (7 days) phase, most notably in moderate injuries (50 kdyne), with overall vesicle counts lower chronically (3 months). CD9 emerged as the predominant tetraspanin sEV marker, while CD63 and CD81 were generally present at low levels across all injury severities and timepoints. Surface sEV analysis revealed dynamic regulation of CD41⁺, CD44⁺, and CD61⁺ in the CD9⁺ sEV subset, suggesting persistent systemic signaling activity. These markers, traditionally associated with platelet function, may also reflect immune or reparative responses following SCI. Our findings highlight the evolving nature of sEV profiles after SCI and support their potential as non-invasive biomarkers for monitoring injury progression. Full article

(This article belongs to the Special Issue Extracellular Vesicles as Biomarkers for Human Disease)

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39 pages, 1388 KiB

Open AccessReview

Neuroprotective Effects of Metformin Through the Modulation of Neuroinflammation and Oxidative Stress

by Sarah Reed, Equar Taka, Selina Darling-Reed and Karam F. A. Soliman

Cells 2025, 14(14), 1064; https://doi.org/10.3390/cells14141064 - 11 Jul 2025

Abstract

Epidemiological studies have shown that individuals with type 2 diabetes have an increased risk of developing neurodegenerative diseases. These diseases and type 2 diabetes share several risk factors. Meanwhile, the antidiabetic drug metformin offers promising neuroprotective effects by reducing oxidative stress and neuroinflammation, [...] Read more.

Epidemiological studies have shown that individuals with type 2 diabetes have an increased risk of developing neurodegenerative diseases. These diseases and type 2 diabetes share several risk factors. Meanwhile, the antidiabetic drug metformin offers promising neuroprotective effects by reducing oxidative stress and neuroinflammation, two significant factors in neurodegenerative diseases. This review examines the mechanisms by which metformin mitigates neuronal damage. Metformin reduces neuroinflammation by inhibiting microglial activation and suppressing proinflammatory cytokines. It also triggers the nuclear factor erythroid-2-related factor-2 (Nrf2) pathway to combat oxidative stress, an essential regulator of antioxidant defenses. These outcomes support the possible neuroprotective roles of metformin in type 2 diabetes-related cognitive decline and conditions like Alzheimer’s disease. Metformin’s therapeutic potential is further supported by its capacity to strengthen the blood–brain barrier’s (BBB’s) integrity and increase autophagic flux. Metformin also offers several neuroprotective effects by targeting multiple pathological pathways. Moreover, metformin is being studied for its potential benefits beyond glycemic control, particularly in the areas of cognition, Alzheimer’s disease, aging, and stroke management. Evidence from both clinical and preclinical studies indicates a complex and multifaceted impact, with benefits varying among populations and depending on underlying disease conditions, making it an appealing candidate for managing several neurodegenerative diseases. Full article

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31 pages, 1549 KiB

Open AccessSystematic Review

Impact of Early-Life Brain Injury on Gut Microbiota Composition in Rodents: Systematic Review with Implications for Neurodevelopment

by Vanessa da Silva Souza, Raul Manhães-de-Castro, Sabrina da Conceição Pereira, Beatriz Souza de Silveira, Caio Matheus Santos da Silva Calado, Henrique José Cavalcanti Bezerra Gouveia, Jacques-Olivier Coq and Ana Elisa Toscano

Cells 2025, 14(14), 1063; https://doi.org/10.3390/cells14141063 - 11 Jul 2025

Abstract

Early-life brain injuries are major causes of long-term neurodevelopmental disorders such as cerebral palsy. Emerging evidence suggests these injuries can alter the gut microbiota composition, intestinal integrity, and neuroinflammatory responses. This systematic review evaluated the impact of early-life brain injuries on the gut [...] Read more.

Early-life brain injuries are major causes of long-term neurodevelopmental disorders such as cerebral palsy. Emerging evidence suggests these injuries can alter the gut microbiota composition, intestinal integrity, and neuroinflammatory responses. This systematic review evaluated the impact of early-life brain injuries on the gut microbiota in rodent models. A scientific literature search was conducted across Medline/PubMed, Web of Science, Scopus, and Embase. Initially, 7419 records were identified, and 21 eligible studies were included. Eligible studies focused on evaluating the microbiota alterations and related gut–brain axis markers at the neonatal or post-weaning stages. The data extraction and synthesis followed PRISMA guidelines. Most studies reported gut dysbiosis characterized by a decreased abundance of Bacteroidetes, and Lactobacillus. Alterations were associated with an increased gut permeability, reduced tight junction proteins, and elevated pro-inflammatory cytokines. Several studies showed reduced levels of short-chain fatty acids and metabolic pathway disruptions. Brain outcomes included neuroinflammation, white matter injury, altered gene expression, and impaired structural integrity. These results suggest that early-life brain injury induces complex alterations in the gut microbiota and its metabolic products, which may contribute to systemic and neuroinflammatory processes. Understanding these interactions offers insights into the pathophysiology of neurodevelopmental disorders and highlights the gut–brain axis as a potential target for early interventions. Full article

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20 pages, 2995 KiB

Open AccessArticle

Standardized Workflow and Analytical Validation of Cell-Free DNA Extraction for Liquid Biopsy Using a Magnetic Bead-Based Cartridge System

by Shivaprasad H. Sathyanarayana, Sarah B. Spracklin, Sophie J. Deharvengt, Donald C. Green, Margery D. Instasi, Torrey L. Gallagher, Parth S. Shah and Gregory J. Tsongalis

Cells 2025, 14(14), 1062; https://doi.org/10.3390/cells14141062 - 11 Jul 2025

Abstract

Circulating cell-free DNA (cfDNA) is an important biomarker for various cancer types, enabling a non-invasive testing approach. However, pre-analytical variables, including sample collection, tube type, processing conditions, and extraction methods, can significantly impact the yield, integrity, and overall quality of cfDNA. This study [...] Read more.

Circulating cell-free DNA (cfDNA) is an important biomarker for various cancer types, enabling a non-invasive testing approach. However, pre-analytical variables, including sample collection, tube type, processing conditions, and extraction methods, can significantly impact the yield, integrity, and overall quality of cfDNA. This study presents a comprehensive analytical validation of a magnetic bead-based, high-throughput cfDNA extraction system, with a focus on assessing its efficiency, reproducibility, and compatibility with downstream molecular applications. The validation was performed using a range of sample types: synthetic cfDNA spiked into DNA-free plasma, multi-analyte ctDNA plasma controls, Seraseq ctDNA reference material in a plasma-like matrix, extraction specificity controls, residual clinical specimen from patients, and samples from healthy individuals stored at room temperature or 4 °C for up to 48 h to assess stability. Extracted cfDNA was analyzed for concentration, percentage, and fragment size, using the Agilent TapeStation. Variant detection was evaluated using a next-generation sequencing (NGS) assay on the Seraseq ctDNA reference material. The results demonstrated high cfDNA recovery rates, consistent fragment size distribution (predominantly mononucleosomal and dinucleosomal), minimal genomic DNA (gDNA) contamination, and strong concordance between detected and expected variants in reference materials. The workflow also showed robust performance under different study parameters, variable sample conditions, including sample stability and integrity. Together, these findings confirm the efficiency and reliability of the evaluated cfDNA extraction system and underscore the importance of standardized pre-analytical workflows for the successful implementation of liquid biopsy for early cancer detection, therapeutic monitoring, and improved patient outcomes. Full article

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

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28 pages, 3018 KiB

Open AccessReview

The Role of Neurohypophysial Hormones in the Endocrine and Paracrine Control of Gametogenesis in Fish

by Maya Zanardini and Hamid R. Habibi

Cells 2025, 14(14), 1061; https://doi.org/10.3390/cells14141061 - 10 Jul 2025

Abstract

Arginine vasopressin (AVP) and oxytocin (OXT) are neuropeptides traditionally recognized for their roles in the control of osmoregulation, blood pressure, lactation, and parturition in mammals. However, growing evidence suggests that AVPand OXT also regulate gonadal functions in teleost fish. Their expression in both [...] Read more.

Arginine vasopressin (AVP) and oxytocin (OXT) are neuropeptides traditionally recognized for their roles in the control of osmoregulation, blood pressure, lactation, and parturition in mammals. However, growing evidence suggests that AVPand OXT also regulate gonadal functions in teleost fish. Their expression in both male and female gonads, the presence of their receptors in ovaries and testes, and their interactions with steroids and other gonadal factors indicate a role in modulating gametogenesis and steroidogenesis via autocrine and paracrine mechanisms. Here, we review the current findings on AVP and OXT in teleost gonads, compared to the observed functions in mammals, emphasizing their systemic interactions within the hypothalamic–pituitary–gonadal (HPG) axis. While highlighting the roles of gonadal AVP and OXT in fish reproduction, we underscore the need for further research to unravel their complex multifactorial regulatory networks. Insights into the vasopressinergic system could enhance aquaculture practices by improving spawning success and reproductive efficiency. Full article

(This article belongs to the Section Reproductive Cells and Development)

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19 pages, 886 KiB

Open AccessReview

A Meta-Review of Spatial Transcriptomics Analysis Software

by Jessica Gillespie, Maciej Pietrzak, Min-Ae Song and Dongjun Chung

Cells 2025, 14(14), 1060; https://doi.org/10.3390/cells14141060 - 10 Jul 2025

Abstract

Spatial transcriptomics combines gene expression data with spatial coordinates to allow for the discovery of detailed RNA localization, study development, investigating the tumor microenvironment, and creating a tissue atlas. A large range of spatial transcriptomics software is available, with little information on which [...] Read more.

Spatial transcriptomics combines gene expression data with spatial coordinates to allow for the discovery of detailed RNA localization, study development, investigating the tumor microenvironment, and creating a tissue atlas. A large range of spatial transcriptomics software is available, with little information on which may be better suited for particular datasets or computing environments. A review was conducted to detail the useful metrics when choosing appropriate software for spatial transcriptomics analysis. Specifically, the results from benchmarking studies that compared software across four key areas of spatial transcriptomics analysis (tissue architecture identification, spatially variable gene discovery, cell–cell communication analysis, and deconvolution) were assimilated into a single review that can serve as guidance when choosing potential spatial transcriptomics analysis software. Full article

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23 pages, 1259 KiB

Open AccessReview

Integrative Review of Molecular, Metabolic, and Environmental Factors in Spina Bifida and Congenital Diaphragmatic Hernia: Insights into Mechanisms and Emerging Therapeutics

by Angelika Buczyńska, Iwona Sidorkiewicz, Przemysław Kosiński, Adam Jacek Krętowski and Monika Zbucka-Krętowska

Cells 2025, 14(14), 1059; https://doi.org/10.3390/cells14141059 - 10 Jul 2025

Abstract

Spina Bifida (SB) and Congenital Diaphragmatic Hernia (CDH) are complex congenital anomalies that pose significant challenges in pediatric healthcare. This review synthesizes recent advancements in understanding the genetic, metabolic, and environmental factors contributing to these conditions, with the aim of integrating mechanistic insights [...] Read more.

Spina Bifida (SB) and Congenital Diaphragmatic Hernia (CDH) are complex congenital anomalies that pose significant challenges in pediatric healthcare. This review synthesizes recent advancements in understanding the genetic, metabolic, and environmental factors contributing to these conditions, with the aim of integrating mechanistic insights into therapeutic innovations. In SB, key findings highlight the roles of KCND3, a critical regulator of spinal cord development, and VANGL2, essential for planar cell polarity and neural tube closure. MicroRNAs such as miR-765 and miR-142-3p are identified as key regulators of these genes, influencing neural development. Additionally, telomere shortening—a marker of cellular senescence—alongside disruptions in folate metabolism and maternal nutritional deficiencies, significantly increases the risk of SB. These findings underscore the crucial role of telomere integrity in maintaining neural tissue homeostasis during embryonic development. For CDH, genetic deletions, including those on chromosome 15q26, and chromosomal abnormalities have been shown to disrupt lung and vascular development, profoundly impacting neonatal outcomes. MicroRNAs miR-379-5p and miR-889-3p are implicated in targeting essential genes such as IGF1 and FGFR2, which play pivotal roles in pulmonary function. Promising emerging therapies, including degradable tracheal plugs and fibroblast growth factor-based treatments, offer potential strategies for mitigating pulmonary hypoplasia and improving clinical outcomes. This review underscores the intricate interplay of genetic, metabolic, and environmental pathways in SB and CDH, identifying critical molecular targets for diagnostics and therapeutic intervention. By integrating findings from genetic profiling, in vitro models, and clinical studies, it aims to inform future research directions and optimize patient outcomes through collaborative, multidisciplinary approaches. Full article

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18 pages, 3083 KiB

Open AccessArticle

Hypergravity and ERK Inhibition Combined Synergistically Reduce Pathological Tau Phosphorylation in a Neurodegenerative Cell Model

by Valerio Mignucci, Ivana Barravecchia, Davide De Luca, Giacomo Siano, Cristina Di Primio, Jack J. W. A. van Loon and Debora Angeloni

Cells 2025, 14(14), 1058; https://doi.org/10.3390/cells14141058 - 10 Jul 2025

Abstract

This study evaluates the effects of hypergravity (HG) on a neurodegenerative model in vitro, looking at how HG influences Tau protein aggregation in Mouse Hippocampal Neuronal Cells (HT22) induced by neurofibrillary tangle seeds. Overall, 50× g significantly, synergistically, reduced the Tau aggregate Area [...] Read more.

This study evaluates the effects of hypergravity (HG) on a neurodegenerative model in vitro, looking at how HG influences Tau protein aggregation in Mouse Hippocampal Neuronal Cells (HT22) induced by neurofibrillary tangle seeds. Overall, 50× g significantly, synergistically, reduced the Tau aggregate Area when combined with ERK-inhibitor PD-0325901, correlating with decreased phosphorylation at critical residues pS262 and pS396. These findings suggest HG treatments may help mitigate cytoskeletal damage linked to Tau aggregation. Full article

(This article belongs to the Special Issue Ageing and Neurodegenerative Diseases, Second Edition)

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47 pages, 2757 KiB

Open AccessReview

Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies

by Dominika Kunachowicz, Paulina Tomecka, Mikołaj Sędzik, Jarosław Kalinin, Jacek Kuźnicki and Nina Rembiałkowska

Cells 2025, 14(14), 1057; https://doi.org/10.3390/cells14141057 - 10 Jul 2025

Abstract

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading [...] Read more.

Hypoxia, characterized by a reduction in tissue oxygen levels, is a hallmark of many solid tumors and affects a range of cellular processes, including DNA repair. In low-oxygen conditions, cancer cells often suppress key DNA repair pathways such as homologous recombination (HR), leading to the accumulation of DNA damage and increased genomic instability. These changes not only drive tumor progression but also contribute to resistance against conventional therapies. Hypoxia significantly reduces the effectiveness of oxygen-dependent treatments, including radiotherapy and many chemotherapeutic agents. To address this limitation, bioreductive drugs have been developed that become selectively activated in hypoxic environments, providing targeted cytotoxic effects within oxygen-deprived tumor regions. Additionally, the rapid growth of tumors often results in disorganized and inefficient vasculature, further impairing the delivery of oxygen and therapeutic agents. This review explores the molecular mechanisms by which hypoxia disrupts DNA repair and contributes to treatment resistance. It also presents emerging therapeutic strategies aimed at targeting the hypoxic tumor microenvironment to improve treatment efficacy and patient outcomes. Full article

(This article belongs to the Section Cell Microenvironment)

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15 pages, 548 KiB

Open AccessArticle

The Role of Cytokine Gene Polymorphisms in Rehabilitation Outcome After Traumatic Brain Injury

by Franca Rosa Guerini, Cristina Agliardi, Milena Zanzottera, Antonio Caronni, Laura Antolini, Chiara Camilla Derchi, Tiziana Atzori, Elisabetta Bolognesi, Jorge Navarro, Mario Clerici and Angela Comanducci

Cells 2025, 14(14), 1056; https://doi.org/10.3390/cells14141056 - 10 Jul 2025

Abstract

Traumatic brain injury (TBI) affects millions of people worldwide and often results in long-term disabilities. Clinical outcomes vary widely even among patients with similar injury severity, partly due to systemic neuroinflammatory responses mediated by pro- and anti-inflammatory cytokines. Genetic polymorphisms in cytokine-coding genes [...] Read more.

Traumatic brain injury (TBI) affects millions of people worldwide and often results in long-term disabilities. Clinical outcomes vary widely even among patients with similar injury severity, partly due to systemic neuroinflammatory responses mediated by pro- and anti-inflammatory cytokines. Genetic polymorphisms in cytokine-coding genes may influence cytokine expression, thereby affecting rehabilitation and prognosis. We analyzed genetic polymorphisms in the TNF-α, IL-6, IL-6 receptor, IL-1β, and IL-10 genes in 28 subacute TBI patients undergoing rehabilitation. Clinical outcomes were assessed using the Glasgow Outcome Scale Extended (GOSE) and domain-specific scales for cognitive, motor, and functional recovery. Results were correlated with genetic profiles to identify potential predictive biomarkers. The IL-6-174 (GG) and IL-6R 1073 (AA) genotypes correlated with worse GOSE scores (p = 0.02 and p = 0.01, respectively). Co-segregation of IL-6-174 - IL-6R 1073 G-A alleles was linked to poorer outcomes (p = 0.01). Patients with the TNF-α-308 (GA) genotype showed less improvement in Barthel and Mobility scores (p = 0.001 and p = 0.01, respectively) and had a higher incidence of post-traumatic confusional state after rehabilitation (p = 0.03). Overall, the TNF-α-308(GA), IL-6 -174(GG), and IL-6R 1073(AA) genotypes negatively impact rehabilitation outcomes, likely due to their role in enhancing neuroinflammation. Larger studies are needed to develop personalized therapies tailored to genetic profiles, aiming to improve rehabilitation outcomes for TBI patients. Full article

(This article belongs to the Special Issue Neuroinflammation in Brain Health and Diseases)

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24 pages, 6634 KiB

Open AccessArticle

Integrated Management of Tomato Fusarium Wilt: Ultrastructure Insights into Zn Nanoparticles and Phytohormone Applications

by Yasmin M. Heikal, Amal M. Albahi, Amal A. Alyamani, Hala M. Abdelmigid, Samia A. Haroun and Hoda M. Soliman

Cells 2025, 14(14), 1055; https://doi.org/10.3390/cells14141055 - 10 Jul 2025

Abstract

Fusarium wilt (FW), induced by Fusarium oxysporum, poses a significant threat to global tomato (Solanum lycopersicum L.) production, leading to substantial yield reduction. This study investigated the anatomical and ultrastructural responses of tomato leaves to FW infection and assessed the efficacy [...] Read more.

Fusarium wilt (FW), induced by Fusarium oxysporum, poses a significant threat to global tomato (Solanum lycopersicum L.) production, leading to substantial yield reduction. This study investigated the anatomical and ultrastructural responses of tomato leaves to FW infection and assessed the efficacy of salicylic acid (SA), humic acid (HA), and zinc oxide nanoparticles (ZnO-NPs) as control and inducer agents. FW infection resulted in notable structural alterations, including decreased leaf blade and mesophyll thickness and increased Adaxial epidermal cell wall thickness, thereby disrupting the leaf structure. Also, it caused severe chloroplast damage, such as membrane detachment and a reduced count of starch granules, which could impair photosynthetic efficiency. The different treatments exhibited significant effectiveness in reversing these adverse effects, leading to increased thickness of the leaf blade, mesophyll, palisade, and spongy tissues and enhanced structural integrity. Furthermore, ultrastructural improvements included activated mitochondria, compact chloroplasts with increased numbers, and proliferation of plastoglobuli, indicating adaptive metabolic changes. Principal component analysis (PCA-biplot) highlighted the significant parameters distinguishing treatment groups, providing insights into trait-based differentiation. This study concluded the potential of SA, HA, and ZnO-NPs as sustainable solutions for managing Fusarium wilt and enhancing tomato plant resilience, thereby contributing to improved agricultural practices and food security. Full article

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

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14 pages, 586 KiB

Open AccessReview

Cues of Trained Immunity in Multiple Sclerosis Macrophages

by Elisa Popa, Hélène Cheval and Violetta Zujovic

Cells 2025, 14(14), 1054; https://doi.org/10.3390/cells14141054 - 10 Jul 2025

Abstract

Multiple sclerosis (MS) is a complex autoimmune disease with both genetic and environmental influences, yet its underlying mechanisms remain only partially understood. In this review, we compile evidence suggesting that trained immunity—a form of innate immune memory—may play a crucial role in the [...] Read more.

Multiple sclerosis (MS) is a complex autoimmune disease with both genetic and environmental influences, yet its underlying mechanisms remain only partially understood. In this review, we compile evidence suggesting that trained immunity—a form of innate immune memory—may play a crucial role in the autoimmune component of MS. By examining key findings from immunology, neuroinflammation, and MS pathophysiology, we explore how innate immune cells, particularly monocytes and macrophages, could contribute to disease onset and progression through persistent pro-inflammatory responses. Understanding the impact of trained immunity in MS could open new avenues for therapeutic strategies targeting the innate immune system. Full article

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

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14 pages, 862 KiB

Open AccessReview

Immune and Inflammatory Properties of Megakaryocytes

by Shiv Vardan Singh, Audrey Lucerne and Katya Ravid

Cells 2025, 14(14), 1053; https://doi.org/10.3390/cells14141053 - 10 Jul 2025

Abstract

Megakaryocytes (MKs), which primarily develop in bone marrow (BM) from hematopoietic stem cells, are critical for platelet production. Beyond their well-established role in thrombopoiesis, MKs have been identified as important for BM niche maintenance, such as by supporting the growth and differentiation of [...] Read more.

Megakaryocytes (MKs), which primarily develop in bone marrow (BM) from hematopoietic stem cells, are critical for platelet production. Beyond their well-established role in thrombopoiesis, MKs have been identified as important for BM niche maintenance, such as by supporting the growth and differentiation of other cell types. Recently, megakaryopoiesis has been reported as yielding divergent subpopulations of MKs, as evidenced by single-cell RNA sequencing of lung, spleen, or BM resident MKs. Interestingly, these subpopulations constitute a significant proportion of “immune MKs” expressing various classical immune markers and capable of phagocytosing pathogens and contributing to antigen presentation. As such, MKs were also found to regulate inflammation, mainly by secreting various cytokines and chemokines to crosstalk with other cell types. The level and functional signature of these “immune MKs” were found to be altered in various pathological conditions, indicative of their purposeful values in health and diseases. In this review, we survey and highlight newly reported functional immune and inflammatory properties of MKs in health and in select pathologies. Full article

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Cells

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