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Cells

Cells is an international, peer-reviewed, open access journal on cell biology, molecular biology, and biophysics, published semimonthly online by MDPI. The Nordic Autophagy Society (NAS) and the Spanish Society of Hematology and Hemotherapy (SEHH) are affiliated with Cells and their members receive discounts on the article processing charges.

Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, MEDLINE, PMC, CAPlus / SciFinder, and other databases.
Journal Rank: JCR - Q2 (Cell Biology) / CiteScore - Q1 (General Biochemistry, Genetics and Molecular Biology)
Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16 days after submission; acceptance to publication is undertaken in 2.7 days (median values for papers published in this journal in the first half of 2025).
Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
Sections: published in 21 topical sections.
Companion journal: Organoids.

Impact Factor: 5.2 (2024); 5-Year Impact Factor: 6.1 (2024)

Imprint Information Journal Flyer Open Access ISSN: 2073-4409

Latest Articles

16 pages, 5496 KiB

Open AccessArticle

MMP-12 Inhibits Inverse Eosinophilic Inflammation-Mediated Bronchial Fibrosis in Murine Models of Pulmonary Airway Obstruction

by Chandra Sekhar Kathera, Chandra Sekhar Yadavalli and Anil Mishra

Cells 2025, 14(17), 1307; https://doi.org/10.3390/cells14171307 (registering DOI) - 23 Aug 2025

Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turnover of the extracellular matrix (ECM). We observed that induced MMP-12 promotes eosinophilic inflammation-related epithelial cell mesenchymal transition (EMT), bronchial fibrosis, and airway obstruction in an allergen-exposed mouse model of [...] Read more.

Matrix metalloproteinases (MMPs) are a major group of proteases known to regulate the turnover of the extracellular matrix (ECM). We observed that induced MMP-12 promotes eosinophilic inflammation-related epithelial cell mesenchymal transition (EMT), bronchial fibrosis, and airway obstruction in an allergen-exposed mouse model of chronic airway diseases in allergen-exposed mice and in airway-specific CC10-IL-13-overexpressed mice. Our histological analysis showed that the parabronchial and perivascular accumulation of eosinophils, fibroblasts, and collagen is significantly decreased in MMP-12^−/− allergen-exposed mice and airway-specific rtTA-MMP-12^−/−CC-10-IL-13-overexpressed mice compared to allergen-exposed wild-type mice and rtTA-CC10-IL-13-overexpressed mice. ELISA and Western blot analyses validated these histological findings, demonstrating that EMT and profibrotic protein levels were significantly decreased in allergen-challenged MMP-12^−/− mice and rtTA-MMP-12^−/−CC10-IL-13-overexpressed mice in comparison to the allergen-exposed wild-type mice and rtTA-CC10-IL-13-overexpressed mice. In addition, we also observed that allergen-challenged MMP-12^−/− mice have improved resistance and compliance compared to allergen-challenged wild-type mice. Most importantly, we show that treatment with MMP-12 inhibitors (PF-00356231 and MMP408) restricts the induction and progression of bronchial fibrosis and airway restrictions in allergen-exposed mice and airway-specific rtTA-CC10-IL-13 mice compared to the respective control mice. Taken together, the novelty of these findings lie in the fact that induced MMP-12 regulates eosinophilic inflammation-induced bronchial fibrosis and associated airway restriction, which may be reduced by treatment with MMP-12 inhibitors. Full article

20 pages, 1451 KiB

Open AccessReview

Impact of Novel Agents on Allogeneic Hematopoietic Cell Transplantation in Patients with T-Cell Lymphomas

by Yoshitaka Inoue and Jun-ichirou Yasunaga

Cells 2025, 14(17), 1306; https://doi.org/10.3390/cells14171306 (registering DOI) - 23 Aug 2025

T-cell lymphomas (TCLs) are generally associated with a poorer prognosis compared to B-cell lymphomas, and allogeneic hematopoietic cell transplantation (allo-HCT) is often considered for eligible patients. One of the primary reasons for the inferior outcomes in TCLs has been the lack of effective [...] Read more.

T-cell lymphomas (TCLs) are generally associated with a poorer prognosis compared to B-cell lymphomas, and allogeneic hematopoietic cell transplantation (allo-HCT) is often considered for eligible patients. One of the primary reasons for the inferior outcomes in TCLs has been the lack of effective novel agents for many years, resulting in a continued reliance on traditional cytotoxic chemotherapy regimens. However, over the past decade, several novel agents with promising efficacy against TCLs have been developed. Notably, many of these agents not only exert direct anti-tumor effects but also modulate host immune function, raising clinical questions regarding the optimal integration of these agents with allo-HCT. In this review, we aim to summarize how the use of novel agents that are approved for the treatment of TCLs—such as mogamulizumab, brentuximab vedotin, lenalidomide, histone deacetylase inhibitors, enhancer of zeste homolog inhibitors, and immune checkpoint inhibitors—before or after allo-HCT may impact transplantation outcomes in patients with TCLs. Full article

(This article belongs to the Special Issue State of the Art and Future Prospects in Stem Cell Transplantation)

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20 pages, 3338 KiB

Open AccessArticle

Discovery and Functional Characterization of Novel Aquaporins in Tomato (Solanum lycopersicum): Implications for Ion Transport and Salinity Tolerance

by Newton Chandra Paul, Shahin Imran, Anri Mitsumoto, Izumi C. Mori and Maki Katsuhara

Cells 2025, 14(17), 1305; https://doi.org/10.3390/cells14171305 - 22 Aug 2025

Aquaporins (AQPs) are membrane proteins that facilitate the transport of water and solutes. Among AQPs, plasma membrane intrinsic proteins (PIPs) play a critical role in maintaining water balance between the internal and external cell environments. This study focuses on the tomato due to [...] Read more.

Aquaporins (AQPs) are membrane proteins that facilitate the transport of water and solutes. Among AQPs, plasma membrane intrinsic proteins (PIPs) play a critical role in maintaining water balance between the internal and external cell environments. This study focuses on the tomato due to its economic importance and cultivation under moderate salinity conditions in Japan. A swelling assay using X. laevis oocyte confirmed that all five examined tomato SlPIP2 isoforms showed water transport activity. Among them, two-electrode voltage clamp (TEVC) experiments showed that only SlPIP2;1, SlPIP2;4, and SlPIP2;8 transport Na⁺ and K⁺, with no transport activity for Cs⁺, Rb⁺, Li⁺, or Cl⁻. CaCl₂ (1.8 mM) reduced ionic currents by approximately 45% compared to 30 µM free-Ca²⁺. These isoforms function as very low-affinity Na⁺ and K⁺ transporters. Expression analysis showed that SlPIP2;4 and SlPIP2;8 had low, stable expression, while SlPIP2;1 was strongly upregulated in roots NaCl treatment (200 mM, 17days), suggesting distinct physiological roles for these ion-conducting AQPs (icAQPs). These data hypothesized that tomato icAQPs play a critical role in ion homeostasis, particularly under salinity stress. In conclusion, the first icAQPs have been identified in the dicotyledonous crop. These icAQPs are essential for plant resilience under salt stress. Full article

(This article belongs to the Special Issue Membrane Dynamics and the Role of Aquaporins in Plant Cells)

30 pages, 11362 KiB

Open AccessArticle

Human Adipose-Stem-Cell-Derived Small Extracellular Vesicles Modulate Behavior and Glial Cells in Young and Aged Mice Following TBI

by Salma S. Abdelmaboud, Lauren D. Moss, Charles Hudson, Rekha Patel, Marta Avlas, Jessica Wohlfahrt, Tiara Wolf, Jennifer Guergues, Stanley M. Stevens, Jr., Niketa A. Patel and Paula C. Bickford

Cells 2025, 14(17), 1304; https://doi.org/10.3390/cells14171304 - 22 Aug 2025

Traumatic brain injury (TBI) is a major cause of long-term neurological impairment, with aging amplifying vulnerability and worsening recovery. Older individuals face greater cognitive and motor deficits post-TBI and respond less effectively to treatments, as both aging and TBI independently elevate neuroinflammation and [...] Read more.

Traumatic brain injury (TBI) is a major cause of long-term neurological impairment, with aging amplifying vulnerability and worsening recovery. Older individuals face greater cognitive and motor deficits post-TBI and respond less effectively to treatments, as both aging and TBI independently elevate neuroinflammation and cognitive decline. This study evaluated the therapeutic effects of human adipose-derived stem cell small extracellular vesicles (hASC-sEVs) on neurological recovery and neuroinflammation in a mouse model of TBI. Male C57BL/6 mice (3, 15, and 20 months old) underwent controlled cortical impact (CCI) and received intranasal hASC-sEVs 48 h post-injury; control groups received PBS. A dose–response study at 7 days post injury (dpi) identified 20 µg as the optimal therapeutic dose, improving motor function, reducing neuroinflammation, and enhancing neurogenesis. This was followed by a 30-dpi study assessing cognitive function, neuroinflammation, neurogenesis, and proteomic changes in microglia and astrocytes via mass spectrometry. hASC-sEV treatment significantly improved behavioral outcomes and reduced neuroinflammatory markers (GFAP, IBA-1, and MHC-II), with reduced efficacy observed in older mice. Proteomics revealed that hASC-sEVs reduce inflammatory proteins (TNF-α, IL-1β, IFNG, CCL2) and modulated mitochondrial dysfunction and reactive oxygen species. These results highlight hASC-sEVs as a promising cell-free therapy for improving TBI outcomes, especially in aging populations. Full article

(This article belongs to the Special Issue Glial Cells: Physiological and Pathological Perspective)

49 pages, 5065 KiB

Open AccessReview

Drosophila as a Model for Studying the Roles of Lamins in Normal Tissues and Laminopathies

by Aleksandra Zielińska, Marta Rowińska, Aleksandra Tomczak and Ryszard Rzepecki

Cells 2025, 14(17), 1303; https://doi.org/10.3390/cells14171303 - 22 Aug 2025

Nuclear processes are fundamental to the regulation of cellular, tissue, and organismal function, especially in complex multicellular systems. Central to these processes are lamins and lamin-associated proteins, which contribute to nuclear structure, gene expression, and chromatin organization. The discovery that mutations in genes [...] Read more.

Nuclear processes are fundamental to the regulation of cellular, tissue, and organismal function, especially in complex multicellular systems. Central to these processes are lamins and lamin-associated proteins, which contribute to nuclear structure, gene expression, and chromatin organization. The discovery that mutations in genes coding for lamins and lamina-associated proteins give rise to rare disorders—collectively called laminopathies—has intensified interest in this field among cell biologists and medical scientists. While many practical and clinically relevant questions about phenotype development and potential treatments require mammalian models, key molecular mechanisms and interactions have also been effectively studied in both vertebrate and invertebrate systems. This review focuses on a discussion of Drosophila lamins, their major properties, functions, interactions and post-translational modifications, with comparison to mammalian lamins, and a discussion of the value of fly models in studies of lamins in muscle tissue development and function in comparison to mammalian lamin B-type and A/C-type. In this paper, we have discussed the overall impact of lamin Dm and lamin C level manipulations on overall phenotype, especially on larval and adult muscles. We have thoroughly discussed the conclusions, which may have been drawn from experiments with overexpression of lamin C mutants mimicking lamin A laminopathy mutations. We have presented and discussed the suggestion that the mechanisms underlying Drosophila muscle phenotype development are similar not only to human dystrophic laminopathies but also to classical human muscular dystrophies such as Duchenne muscular dystrophy and Hutchison–Gilford Progeria syndrome. We suggest that the activation of the stress response contributes to the laminopathic phenotype detected in Drosophila. Finely, this review discusses in depth the lamin Dm and lamin C interactomes, discrepancies between String-based interactome networks, and our map of interactomes based on manual verification of experimental data on Drosophila lamin interactions. Full article

(This article belongs to the Section Cellular Biophysics)

24 pages, 34589 KiB

Open AccessArticle

Extracellular Vesicle-Mediated miR-155 from Visceral Adipocytes Induces Skeletal Muscle Dysplasia in Obesity

by Yunyan Ji, Zeen Gong, Rui Liang, Di Wu, Wen Sun, Xiaomao Luo, Yi Yan, Jiayin Lu, Juan Wang and Haidong Wang

Cells 2025, 14(17), 1302; https://doi.org/10.3390/cells14171302 - 22 Aug 2025

Obesity poses a serious threat to human health, with induced skeletal muscle dysfunction significantly increasing the risk of metabolic syndrome. In obesity, it is known that visceral adipose tissue (VAT) mediates the dysregulation of the adipose–muscle axis through exosome-delivered miRNAs, but the associated [...] Read more.

Obesity poses a serious threat to human health, with induced skeletal muscle dysfunction significantly increasing the risk of metabolic syndrome. In obesity, it is known that visceral adipose tissue (VAT) mediates the dysregulation of the adipose–muscle axis through exosome-delivered miRNAs, but the associated regulatory mechanisms remain incompletely elucidated. This study established an AAV-mediated miR-155 obese mouse model and a co-culture system (HFD VAD-evs/RAW264.7 cells/C2C12 cells) to demonstrate that high-fat diet-induced VA-derived extracellular vesicles (HFD VAD-evs) preferentially accumulate in skeletal muscle and induce developmental impairment. HFD VAD-evs disrupt skeletal muscle homeostasis through dual mechanisms: the direct suppression of myoblast development via exosomal miR-155 cargo and the indirect inhibition of myogenesis through macrophage-mediated inflammatory responses in skeletal muscle. Notably, miR-155 inhibition in HFD VAD-evs reversed obesity-associated myogenic deficits. These findings provide novel mechanistic insights into obesity-induced skeletal muscle dysregulation and facilitate potential therapeutic strategies targeting exosomal miRNA signaling. Full article

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20 pages, 1149 KiB

Open AccessReview

Calpain-1 and Calpain-2 in the Brain: What Have We Learned from 45 Years of Research?

by Michel Baudry and Xiaoning Bi

Cells 2025, 14(17), 1301; https://doi.org/10.3390/cells14171301 - 22 Aug 2025

Although the calcium-dependent proteases, calpains, were discovered more than 60 years ago, we still know very little regarding their functions, mostly because very few studies are addressing questions related to specific members of this relatively large family of cysteine proteases. The “classical calpains”, [...] Read more.

Although the calcium-dependent proteases, calpains, were discovered more than 60 years ago, we still know very little regarding their functions, mostly because very few studies are addressing questions related to specific members of this relatively large family of cysteine proteases. The “classical calpains”, calpain-1 and calpain-2, are ubiquitous and have received more attention because of the special roles they play in the brain. The authors have been studying the properties and functions of these two calpain isoforms in the brain for over 45 years, and this review will focus on what has been learned over this period of time. In particular, we will discuss the numerous studies that have led to the notion that calpain-1 and calpain-2 play opposite functions in the brain on processes ranging from neuronal survival or death, synaptic plasticity, and learning and memory to neurogenesis. Mechanisms underlying these opposite functions are starting to be understood and the findings support the notion that such opposite functions might be a general feature of these two isoforms in any type of cell. This review concludes with a discussion of the potential benefits of selective calpain-2 inhibitors for the treatment of a variety of neurological disorders. Full article

(This article belongs to the Special Issue Role of Calpains in Health and Diseases)

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18 pages, 3480 KiB

Open AccessArticle

Retinoic Acid Modulates Immune Differentiation in a Human Small Intestinal In Vitro Model

by Christa Schimpel, Christina Passegger, Carmen Tam-Amersdorfer and Herbert Strobl

Cells 2025, 14(17), 1300; https://doi.org/10.3390/cells14171300 - 22 Aug 2025

Retinoic acid (RA) plays a key role in mucosal immune regulation and tolerance, with implications for inflammatory bowel disease (IBD). However, its effects have not been extensively studied in humanized in vitro models that recapitulate epithelial–immune interactions. We established a 3D in vitro [...] Read more.

Retinoic acid (RA) plays a key role in mucosal immune regulation and tolerance, with implications for inflammatory bowel disease (IBD). However, its effects have not been extensively studied in humanized in vitro models that recapitulate epithelial–immune interactions. We established a 3D in vitro small intestinal model composed of three epithelial cell types, naïve CD4⁺ T cells, and monocyte/dendritic cell (M/DC) precursors derived from CD34⁺ umbilical cord blood hematopoietic stem/progenitor cells. The epithelial microenvironment strongly suppressed monocyte/DC differentiation and T cell activation, indicating a regulatory role of epithelial-derived signals. Retinoic acid (RA) priming of M/DC precursors induced CD103⁺CD11b⁺Sirp1α⁻ regulatory DCs and promoted a shift from naive to memory-type T cells. Upon addition of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β), the model mimicked an inflamed intestinal state, resulting in CD14⁺CD16⁺ inflammatory monocytes and increased T cell activation (CD25⁺CD69⁺). RA-primed DCs modestly counterbalanced T cell activation and IBD-like responses, even under inflammatory conditions. Flow cytometry and clustering analysis revealed distinct immune cell phenotypes depending on RA exposure and cytokine context. This model provides a reproducible and physiologically relevant human system to study RA-mediated immune programming in the intestinal mucosa and may support the development of novel therapeutic strategies for IBD and related inflammatory conditions. Statistical differences were evaluated using ANOVA with Tukey’s post-hoc test (n = 4; p < 0.05). Full article

(This article belongs to the Section Cell Microenvironment)

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24 pages, 1513 KiB

Open AccessArticle

Selective Anticancer Activity and Safety Profile of Chlorochalcones: Impact on Breast Cancer, Blood, and Endothelial Cells

by Sylwia Cyboran-Mikołajczyk, Karolina Matczak, Teresa Kaźmierczak, Natalia Trochanowska-Pauk, Tomasz Walski, Raghvendra Bohara, Karol Bukowski, Agnieszka Krawczyk-Łebek and Edyta Kostrzewa-Susłow

Cells 2025, 14(16), 1299; https://doi.org/10.3390/cells14161299 - 21 Aug 2025

In the pursuit of novel anticancer therapies, assessing their selectivity and safety profile towards healthy cells is crucial. This study investigated chlorochalcones, derivatives of 2′-hydroxychalcone containing a chlorine atom, for their impact on human breast cancer cells (MCF-7 and MDA-MB-231), healthy blood cells [...] Read more.

In the pursuit of novel anticancer therapies, assessing their selectivity and safety profile towards healthy cells is crucial. This study investigated chlorochalcones, derivatives of 2′-hydroxychalcone containing a chlorine atom, for their impact on human breast cancer cells (MCF-7 and MDA-MB-231), healthy blood cells (erythrocytes, peripheral blood mononuclear cells (PBMCs), platelets), and microvascular endothelial cells (HMEC-1). Our findings demonstrated that chlorochalcones did not detrimentally affect erythrocytes, showing no hemolysis or preserving osmotic resistance and transmembrane potential. They also exhibited minimal impact on normal PBMC viability and varying effects on platelet metabolic activity at therapeutic concentrations. Importantly, these derivatives displayed lower toxicity towards HMEC-1 endothelial cells than towards breast cancer cells, indicating a degree of selectivity. Chlorochalcones have high antiproliferative activity against cancer cells, primarily by inducing apoptosis with virtually no significant impact on cell cycle progression. Their mechanism of action involves the modulation of reactive oxygen species (ROS) levels and induction of mitochondrial dysfunction, including membrane depolarization and reduced mitochondrial mass. Biological activity, including toxicity and ROS modulation, is dependent on the position and number of chlorine atoms. In conclusion, this study highlights the ability of chlorochalcones to effectively target malignant cells while sparing normal circulatory and endothelial cells, thus positioning them as a promising class of candidates for further anticancer drug development. Full article

(This article belongs to the Section Cellular Biophysics)

12 pages, 3596 KiB

Open AccessArticle

A Novel Role of Protecadherin-7 in Regulation of Pydc3 Expression and the IFN-β Response During Osteoclast Differentiation

by Hyunsoo Kim, Noriko Takegahara and Yongwon Choi

Cells 2025, 14(16), 1298; https://doi.org/10.3390/cells14161298 - 21 Aug 2025

Protocadherin-7 (Pcdh7) is a member of the protocadherin family, a subgroup of the cadherin superfamily. We previously demonstrated that Pcdh7 functions as a signaling receptor in osteoclast differentiation. In this study, we investigated the potential gene regulatory role of Pcdh7 in this process [...] Read more.

Protocadherin-7 (Pcdh7) is a member of the protocadherin family, a subgroup of the cadherin superfamily. We previously demonstrated that Pcdh7 functions as a signaling receptor in osteoclast differentiation. In this study, we investigated the potential gene regulatory role of Pcdh7 in this process and identified Pyrin domain-containing protein 3 (Pydc3) as a key mediator of Pcdh7-mediated regulation of osteoclast differentiation. Differential gene expression analysis comparing wild-type (Pcdh7^+/+) and Pcdh7-deficient (Pcdh7^−/−) cells revealed a significant upregulation of Pydc3 in Pcdh7^−/− cells. RNAi-mediated knockdown of Pydc3 rescued the impaired osteoclast differentiation in Pcdh7^−/− cells, whereas overexpression of Pydc3 suppressed osteoclast differentiation in Pcdh7^+/+ cells, suggesting that Pydc3 negatively regulates osteoclast differentiation. Additionally, Pcdh7^−/− cells showed elevated expression of interferon response genes and increased production of interferon-β (IFN-β). Neutralization of IFN-β signaling using anti-IFN-β and/or anti-interferon alpha and beta receptor 1 (IFNAR1) antibodies significantly restored osteoclast differentiation in Pcdh7^−/− cells. Collectively, these findings uncover a novel role for Pcdh7 in osteoclast differentiation through regulation of Pydc3 expression and IFN-β production. Full article

(This article belongs to the Section Cell Signaling)

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17 pages, 1193 KiB

Open AccessReview

Tissue-Resident Memory T Cells in Cancer Metastasis Control

by Tyler H. Montgomery, Anuj P. Master, Zeng Jin, Qiongyu Shi, Qin Lai, Rohan Desai, Weizhou Zhang, Chandra K. Maharjan and Ryan Kolb

Cells 2025, 14(16), 1297; https://doi.org/10.3390/cells14161297 - 21 Aug 2025

Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in [...] Read more.

Tissue-resident memory T (TRM) cells have emerged as critical sentinels in the control of cancer metastasis, yet their precise roles across different tumor types and tissues remain underappreciated. Here, we review current insights into the mechanisms governing TRM cell seeding and retention in pre-metastatic niches, their effector functions in eliminating disseminated tumor cells, and their dynamic crosstalk with local stromal and myeloid populations. Here, we highlight evidence for organ-specific variability in TRM cell-mediated immunity, discuss strategies for therapeutically harnessing these cells—ranging from vaccination and checkpoint modulation to chemokine axis manipulation—and explore their promise as prognostic biomarkers. Finally, we outline key knowledge gaps and future directions aimed at translating TRM cell biology into targeted interventions to prevent and treat metastatic disease. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Immune Regulation)

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15 pages, 1709 KiB

Open AccessArticle

N-Lactoyl Phenylalanine Disrupts Insulin Signaling, Induces Inflammation, and Impairs Mitochondrial Respiration in Cell Models

by Laila Hedaya, Khaled Naja, Shamma Almuraikhy, Najeha Anwardeen, Asma A. Elashi, Maha Al-Asmakh, Susu M. Zughaier, Meritxell Espino-Guarch, Osama Y. Aldirbashi, Gavin P. Davey and Mohamed A. Elrayess

Cells 2025, 14(16), 1296; https://doi.org/10.3390/cells14161296 - 20 Aug 2025

N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This [...] Read more.

N-lactoyl amino acids (Lac-AAs) are key players that regulate appetite and body weight. The most prominent and well-studied member is N-lactoyl phenylalanine (Lac-Phe), which can be induced by food intake, exercise and metformin treatment. However, its broader metabolic impact remains insufficiently characterized. This study investigates the effects of Lac-Phe on insulin signaling, inflammation, and mitochondrial respiration using HepG2 and differentiated C2C12 cell models, as well as isolated rat brain mitochondria and synaptosomes. Our results demonstrate that Lac-Phe significantly impairs insulin-stimulated phosphorylation of key proteins in the insulin signaling pathway, particularly in skeletal muscle cells, indicating disrupted insulin signaling. Additionally, Lac-Phe exposure increases the secretion of pro-inflammatory cytokines in C2C12 skeletal muscle cells and markedly impairs mitochondrial respiration in HepG2 liver cells and rat brain-derived synaptosomes, but not in isolated mitochondria. These findings highlight potential adverse metabolic effects of Lac-Phe, especially when administered at high concentrations, and underscore the necessity of conducting a comprehensive risk assessment and dose optimization before considering Lac-Phe or related Lac-AAs as therapeutic agents. Our work provides important insights into the molecular liabilities associated with Lac-Phe and calls for further studies to balance its therapeutic promise against possible metabolic risks. Full article

(This article belongs to the Special Issue Biomarkers and Therapeutic Targets in Insulin Resistance)

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20 pages, 4840 KiB

Open AccessArticle

The Function of Transforming Growth Factor 2 in Facilitating Inflammasome Activation to Enhance the Development of Myopia via Complement System

by Sheng-Chun Lin, Yu-An Hsu, Chi-Fong Lin, Chih-Sheng Chen, Peng-Tai Tien, Yao-Chien Wang, Ching-Yao Chang, En-Shyh Lin, Jamie Jiin-Yi Chen, Ming-Yen Wu, Hui-Ju Lin and Lei Wan

Cells 2025, 14(16), 1295; https://doi.org/10.3390/cells14161295 - 20 Aug 2025

Myopia is one of the major public health conditions with significant complications. This study investigates the role of transforming growth factor (TGF)-β2, complement activation, and inflammasome pathways in myopia progression using a Brown Norway rat model. Myopia was induced, and complement regulation was [...] Read more.

Myopia is one of the major public health conditions with significant complications. This study investigates the role of transforming growth factor (TGF)-β2, complement activation, and inflammasome pathways in myopia progression using a Brown Norway rat model. Myopia was induced, and complement regulation was manipulated using gene therapy via adeno-associated virus (AAV) vectors delivering CD55 or CD55 siRNA. Results showed that TGF-β2 exacerbated myopia by upregulating complement components C3 and C5, suppressing CD55, and activating inflammasome pathways through nuclear factor (NF)-κB signaling, leading to axial elongation and increased refractive errors. Overexpression of CD55 via AAV gene therapy effectively counteracted these effects, reducing axial length elongation and inflammation by suppressing inflammasome markers interleukin (IL)-1β and NLR family pyrin domain containing 3 (NLRP3), as confirmed by real-time quantitative PCR and immunofluorescence analyses. Conversely, silencing CD55 intensified TGF-β2-induced effects, further promoting axial elongation and inflammation. These findings highlight the critical role of CD55 in modulating TGF-β2-driven complement and inflammasome activation during myopia progression. The study suggests that gene therapy targeting CD55 could serve as a novel therapeutic strategy to mitigate myopia and related inflammatory processes, offering a promising avenue for managing this significant public health challenge. Full article

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22 pages, 6193 KiB

Open AccessArticle

Cilastatin Modulates DPEP1- and IQGAP1-Associated Neuro-Glio-Vascular Inflammation in Oxaliplatin-Induced Peripheral Neurotoxicity

by Rita Martín-Ramírez, María Ángeles González-Nicolás, Karen Álvarez-Tosco, Félix Machín, Julio Ávila, Manuel Morales, Alberto Lázaro and Pablo Martín-Vasallo

Cells 2025, 14(16), 1294; https://doi.org/10.3390/cells14161294 - 20 Aug 2025

Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) [...] Read more.

Oxaliplatin-induced peripheral neurotoxicity (OIPN) represents a major challenge in cancer therapy, characterized by dorsal root ganglia (DRG) inflammation and disruption of neuro-glio-vascular unit function. In this study, we investigated the involvement of the scaffold protein IQ Motif Containing GTPase Activating Protein 1 (IQGAP1) and dehydropeptidase-1 (DPEP1) in the DRG response to oxaliplatin (OxPt) and the modulatory effect of cilastatin. Behavioral assessment showed a robust nocifensive response to cold stimuli in OxPt-treated rats, attenuated by cilastatin co-treatment. Our confocal study revealed different cellular and subcellular expression patterns of IQGAP1 and DPEP1 in neurons, glia, and endothelial cells, where both signals overlap approximately one-third. OxPt enhanced cytosolic aggregation of IQGAP1 in neurons and upregulation of signal in glia, accompanied by co-expression of TNFα and IL-6, indicating involvement in the inflammatory process. DPEP1 showed altered subcellular distribution in OxPt-treated animals, suggesting a potential role in the inflammatory cascade. Notably, IQGAP1 expression was diminished in endothelial membranes under OxPt, while cilastatin preserved endothelial IQGAP1-CD31 colocalization, suggesting partial restoration of blood-nerve barrier integrity. These findings identify IQGAP1 and DPEP1 as key players in DRG inflammation and position cilastatin as a promising modulator of OIPN through neuro-glio-vascular stabilization. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Neuropathic Pain)

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25 pages, 2729 KiB

Open AccessArticle

Therapeutic Effects of Neuro-Cells on Amyloid Pathology, BDNF Levels, and Insulin Signalling in APPswe/PSd1E9 Mice

by Johannes P. J. M. de Munter, Andrey Tsoy, Kseniia Sitdikova, Erik Ch. Wolters, Kirill Chaprov, Konstantin B. Yenkoyan, Hamlet Torosyan, Sholpan Askarova, Daniel C. Anthony and Tatyana Strekalova

Cells 2025, 14(16), 1293; https://doi.org/10.3390/cells14161293 - 20 Aug 2025

Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34⁺ HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer’s [...] Read more.

Stem cell therapies, including mesenchymal (MSCs) and haematopoietic stem cells (HSCs), have shown promise in neurodegenerative diseases. Here, we investigated the therapeutic effects of a defined combination of unmanipulated MSCs and CD34⁺ HSCs, termed Neuro-Cells (NC), in a murine model of Alzheimer’s disease (AD), the APPswe/PS1dE9 mouse. At 12 months of age, mice received intracisternal injections of NC (1.39 × 10⁶ MSCs + 5 × 10⁵ HSCs) or vehicle. After 45 days, behavioural testing, immunohistochemical analyses of amyloid plaque density (APD), and cortical gene expression profiling were conducted. NC-treated APP/PS1 mice exhibited preserved object recognition memory and reduced anxiety-like behaviours, contrasting with deficits observed in untreated transgenic controls. Histologically, NC treatment significantly reduced the density of small amyloid plaques (<50 μm²) in the hippocampus and thalamus, and total plaque burden in the thalamus. Gene expression analysis revealed that NC treatment normalised or reversed disease-associated changes in insulin receptor (IR) signalling and neurotrophic pathways. Specifically, NC increased expression of Bdnf, Irs2, and Pgc-1α, while attenuating aberrant upregulation of Insr, Igf1r, and markers of ageing and AD-related pathology (Sirt1, Gdf15, Arc, Egr1, Cldn5). These findings indicate that NC therapy mitigates behavioural and molecular hallmarks of AD, potentially via restoration of BDNF and insulin receptor-mediated signalling. Full article

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

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21 pages, 2581 KiB

Open AccessReview

Post-Translational Modifications in Mammalian Folliculogenesis and Ovarian Pathologies

by Dake Chen, Yue Feng, Junjing Wu, Jiawei Zhou, Zipeng Li, Mu Qiao, Tong Chen, Zhong Xu, Xianwen Peng and Shuqi Mei

Cells 2025, 14(16), 1292; https://doi.org/10.3390/cells14161292 - 20 Aug 2025

Post-translational modifications (PTMs) of proteins, as the core mechanism for dynamically regulating follicular development, affect the maintenance of mammalian fertility by precisely coordinating granulosa cell–oocyte interaction, metabolic reprogramming, and epigenetic remodeling. Dysregulation of these modifications directly contributes to major reproductive diseases, including polycystic [...] Read more.

Post-translational modifications (PTMs) of proteins, as the core mechanism for dynamically regulating follicular development, affect the maintenance of mammalian fertility by precisely coordinating granulosa cell–oocyte interaction, metabolic reprogramming, and epigenetic remodeling. Dysregulation of these modifications directly contributes to major reproductive diseases, including polycystic ovary syndrome (PCOS) and premature ovarian insufficiency (POI). Post-translational modifications regulate follicular development through intricate mechanisms. Thus, this review systematically synthesizes recent advances in PTMs, encompassing traditional ones such as phosphorylation, ubiquitination, and acetylation, alongside emerging modifications including lactylation, SUMOylation, and ISGylation, thereby constructing a more comprehensive PTM landscape of follicular development. Furthermore, this study dissects the molecular interaction networks of these PTMs during follicular activation, maturation, and ovulation, and uncovers the common mechanisms through which PTM dysregulation contributes to pathological conditions, including hyperandrogenism in PCOS and follicular depletion in POI. Finally, this review ultimately provides a theoretical basis for improving livestock reproductive efficiency and precise intervention in clinical ovarian diseases. Full article

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20 pages, 4459 KiB

Open AccessArticle

Substrate Stiffness Modulates Hypertrophic Chondrocyte Reversion and Chondrogenic Phenotype Restoration

by Da-Long Dong and Guang-Zhen Jin

Cells 2025, 14(16), 1291; https://doi.org/10.3390/cells14161291 - 20 Aug 2025

The stiffness of the extracellular matrix (ECM) plays a pivotal role in the progression of osteoarthritis (OA), particularly by promoting hypertrophic differentiation of chondrocytes, which hinders cartilage regeneration and accelerates pathological ossification. This study aimed to investigate how substrate stiffness modulates hypertrophic chondrocyte [...] Read more.

The stiffness of the extracellular matrix (ECM) plays a pivotal role in the progression of osteoarthritis (OA), particularly by promoting hypertrophic differentiation of chondrocytes, which hinders cartilage regeneration and accelerates pathological ossification. This study aimed to investigate how substrate stiffness modulates hypertrophic chondrocyte behavior and whether it can reverse their phenotype towards a more stable, chondrogenic state. A series of tunable polydimethylsiloxane (PDMS) substrates with stiffnesses ranging from 78 to 508 kPa were fabricated to simulate varying mechanical microenvironments. Hypertrophic chondrocytes were cultured on these substrates, and their morphology, nuclear architecture, gene/protein expression, and mechanotransductive signaling pathways were systematically evaluated. After 7 to 21 days of culture, the chondrocytes on stiffer matrices exhibited enlarged nuclei, increased cytoskeletal tension, and enhanced focal adhesion signaling. This corresponded with the upregulation of osteogenic and hypertrophic markers such as RUNX2, COL10A1, and COL1A1. In contrast, cells on softer substrates (78 kPa) displayed reduced nuclear YAP localization, higher levels of phosphorylated YAP, and significantly increased expression of COL2A1 and SOX9, indicating reversion to a chondrogenic phenotype. Furthermore, differential activation of Smad1/5/8 and Smad2/3 pathways was observed depending on matrix stiffness, contributing to the phenotype shift. Matrix stiffness exerts a significant regulatory effect on hypertrophic chondrocytes via YAP-mediated mechanotransduction. Soft substrates promote phenotype reversion and cartilage-specific gene expression, offering a promising biomechanical strategy for cartilage tissue engineering and OA intervention. Full article

(This article belongs to the Special Issue Targeting Cellular Microenvironment in Aging and Disease)

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25 pages, 706 KiB

Open AccessReview

The Roles of Non-Coding RNAs in the Pathogenesis of Uterine Fibroids

by Drake Boos, Tsai-Der Chuang and Omid Khorram

Cells 2025, 14(16), 1290; https://doi.org/10.3390/cells14161290 - 20 Aug 2025

Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with Black women being affected at a disproportionate rate. The growth of these tumors is driven by estrogen and progesterone. Driver mutations in genes such as MED12, HMGA2, and FH also [...] Read more.

Uterine fibroids are benign smooth muscle tumors that affect ~70% of women, with Black women being affected at a disproportionate rate. The growth of these tumors is driven by estrogen and progesterone. Driver mutations in genes such as MED12, HMGA2, and FH also play roles in the development and growth of fibroids. Despite their high prevalence, the pathogenesis of fibroids remains largely unknown, leading to a lack of effective therapeutic options. Non-coding RNAs (ncRNAs), including miRNAs (e.g., miR-21, miR-29, miR-200), lncRNAs (e.g., H19, MIAT, XIST), and circRNAs, are important regulatory RNAs that are becoming increasingly implicated in the aberrant expression of protein-coding genes functionally associated with ECM production, cell proliferation, apoptosis, and inflammation in fibroids. Race/ethnicity, MED12 mutations, and ovarian steroids influence the expression of ncRNA expression, further implicating their relevance to fibroid pathogenesis. Therapeutic targeting of these dysregulated ncRNAs in fibroids could enable more precise and individualized non-hormonal-based treatment for this common gynecologic tumor. Full article

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19 pages, 3702 KiB

Open AccessArticle

Kisspeptin Mitigates Hepatic De Novo Lipogenesis in Metabolic Dysfunction-Associated Steatotic Liver Disease

by Kimberly Izarraras, Ankit Shah, Kavita Prasad, Helena Tan, Zhongren Zhou and Moshmi Bhattacharya

Cells 2025, 14(16), 1289; https://doi.org/10.3390/cells14161289 - 20 Aug 2025

The peptide hormone kisspeptin, signaling via its receptor, KISS1R, decreases hepatic steatosis and protects against metabolic dysfunction-associated steatotic liver disease (MASLD). Enhanced de novo lipogenesis (DNL) contributes to MASLD. Here, we investigated whether kisspeptin treatment in obese, diabetic mice directly attenuates DNL. DNL [...] Read more.

The peptide hormone kisspeptin, signaling via its receptor, KISS1R, decreases hepatic steatosis and protects against metabolic dysfunction-associated steatotic liver disease (MASLD). Enhanced de novo lipogenesis (DNL) contributes to MASLD. Here, we investigated whether kisspeptin treatment in obese, diabetic mice directly attenuates DNL. DNL was assessed in kisspeptin-treated mouse livers, using a mouse model of MASLD, (DIAMOND mice), employing ²H₂O-enriched water, mass spectrometry analysis, and transcriptomic profiling. Gene and protein expression were evaluated in primary hepatocytes and livers. Additionally, hepatic Kiss1r expression was increased in DIAMOND mice, following which various biochemical and metabolic assessments were employed. Metabolic tracing in kisspeptin-treated steatotic livers demonstrated a decrease in the DNL of free fatty acids (FFAs), known to be associated with diabetes, steatosis, and hepatocellular carcinoma. Transcriptomic profiling of kisspeptin-treated livers identified disruption of key metabolic pathways, the most prominent being a decrease in fatty acid metabolism, and downregulation of Cidea, a key regulator of lipid droplet formation. Kisspeptin treatment of FFA-loaded primary mouse hepatocytes significantly decreased Cidea expression. Mechanistically, we found that kisspeptin administration decreased levels of transcription factor SREBP-1c, a crucial regulator of DNL, and CIDEA. Thus, enhanced KISS1R signaling limits hepatic DNL, suggesting a crucial role in restricting MASLD. Full article

(This article belongs to the Section Cellular Metabolism)

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24 pages, 3831 KiB

Open AccessReview

Therapeutic Strategies Targeting Aerobic Glycolysis in Cancer and Dynamic Monitoring of Associated Metabolites

by Mengjie Hu, Kaijie Zheng, Lijiao Zhang, Yue Kan, Jiaqian Zhao and Dajing Chen

Cells 2025, 14(16), 1288; https://doi.org/10.3390/cells14161288 - 19 Aug 2025

Cancer cells predominantly utilize aerobic glycolysis for energy production, preferentially converting glucose (Glu) to pyruvate (PA) and subsequently to lactate (LA). This metabolic reprogramming results in extracellular LA accumulation, acidifying the tumor microenvironment (TME) and facilitating tumor invasion and metastasis. The dynamics of [...] Read more.

Cancer cells predominantly utilize aerobic glycolysis for energy production, preferentially converting glucose (Glu) to pyruvate (PA) and subsequently to lactate (LA). This metabolic reprogramming results in extracellular LA accumulation, acidifying the tumor microenvironment (TME) and facilitating tumor invasion and metastasis. The dynamics of Glu, PA, and LA are pivotal to tumor initiation and progression. This review comprehensively discussed therapeutic strategies targeting these key metabolites and systematically evaluates electrochemical and fluorescence-based techniques for their dynamic monitoring. We highlight the critical role of these monitoring approaches in advancing early cancer diagnosis, enabling personalized treatment, and accelerating anticancer drug development. Full article

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