Cells

20 pages, 10200 KB

Open AccessArticle

Small Molecule Cocktail DLC79 Suppresses Gliomagenesis by Activating Ascl1 and Remodeling Transcriptome

by Chuxiao Mao, Zhancheng Deng, Zhuming Chen, Lirong Huang, Caiyun Wang, Gong Chen and Qingsong Wang

Cells 2026, 15(2), 211; https://doi.org/10.3390/cells15020211 - 22 Jan 2026

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Abstract

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified [...] Read more.

Glioblastoma (GBM) remains incurable due to its invasive growth and therapeutic resistance. While the neurogenic transcription factor-mediated reprogramming of glioma cells has been reported, pharmacological reprogramming offers a promising alternative due to its potential advantages for clinical translation. Using phenotype-driven screening, we identified a multi-target small-molecule cocktail DLC79 (DAPT, LDN193189, CHIR99021, I-BET762, and Isx9) that effectively reprograms human glioma cells into neuron-like cells by activating endogenous ASCL1 (174.4-fold) and remodeling the transcriptional landscape. This conversion led to the strong upregulation of neuronal markers (e.g., MAP2 and GAD67) and suppression of glial identity. Functionally, DLC79 treatment inhibited glioma malignancy in vitro, impairing proliferation, migration, invasion, and clonogenicity. In a subcutaneous xenograft model, brief pretreatment with DLC79 significantly attenuated the tumorigenic potential of glioma cells, reducing tumor bioluminescence by 56% and tumor mass by 47%. Our study establishes pharmacological reprogramming as a promising anti-glioma strategy that leverages neuronal conversion to reduce oncogenic properties, thereby initiating a novel therapeutic paradigm. Full article

(This article belongs to the Topic Advances in Glioblastoma: From Biology to Therapeutics)

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13 pages, 2044 KB

Open AccessArticle

Establishing a Non-Surgical Mouse Model of Laryngopharyngeal Reflux Disease: Acid-Induced Epithelial Disruption and Protective Role of N-Acetylcysteine

by You Yeon Chung, Byoungjae Kim, Juhyun Lee, Sooun Kwak, Mingeun Jung, Yeon Soo Kim and Seung-Kuk Baek

Cells 2026, 15(2), 210; https://doi.org/10.3390/cells15020210 - 22 Jan 2026

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Abstract

Laryngopharyngeal reflux disease (LPRD) results from the retrograde flow of gastric contents into the upper aerodigestive tract, causing epithelial injury. Progress in its management has been limited by the lack of objective biomarkers and reproducible in vivo models. This study aimed to establish [...] Read more.

Laryngopharyngeal reflux disease (LPRD) results from the retrograde flow of gastric contents into the upper aerodigestive tract, causing epithelial injury. Progress in its management has been limited by the lack of objective biomarkers and reproducible in vivo models. This study aimed to establish a chronic, non-surgical mouse model of LPRD and to investigate the protective effect of N-acetylcysteine (NAC). Female C57BL/6 mice were randomly assigned to three groups: control (standard drinking water), study (acidified water, pH 3.0, for 12 weeks), and treatment (acidified water for 12 weeks plus NAC supplementation during the final 4 weeks). Body weight, food intake, and water consumption were monitored weekly. Pharyngeal tissues were analyzed by immunohistochemistry and Western blotting. Chronic acid exposure resulted in loss of membrane-localized E-cadherin, cytoplasmic redistribution, and upregulation of matrix metalloproteinase-7 (MMP-7). These molecular alterations were accompanied by enhanced phosphorylation of ERK and c-Jun, consistent with activation of the ROS–ERK–c-Jun signaling pathway. NAC supplementation was associated with partial restoration of E-cadherin, reduced MMP-7 expression, and attenuation of ERK/c-Jun phosphorylation. No systemic toxicity or weight loss was observed, indicating good tolerability of the model. This non-surgical ingestion-based model faithfully recapitulates key epithelial features of LPRD and provides a feasible platform for mechanistic investigation and exploratory therapeutic studies. NAC may exert protective effects against acid-induced epithelial injury in this model. Full article

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

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16 pages, 1456 KB

Open AccessArticle

Cell Density-Dependent Suppression of Perlecan and Biglycan Expression by Gold Nanocluster in Vascular Endothelial Cells

by Takato Hara, Misato Saeki, Misaki Shirai, Yuichi Negishi, Chika Yamamoto and Toshiyuki Kaji

Cells 2026, 15(2), 209; https://doi.org/10.3390/cells15020209 - 22 Jan 2026

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Abstract

Proteoglycans are macromolecules consisting of a core protein and one or more glycosaminoglycan side chains. Proteoglycans synthesized by vascular endothelial cells modulate various functions such as anticoagulant activity and vascular permeability. We previously reported that some heavy metals interfere with proteoglycan expression, and [...] Read more.

Proteoglycans are macromolecules consisting of a core protein and one or more glycosaminoglycan side chains. Proteoglycans synthesized by vascular endothelial cells modulate various functions such as anticoagulant activity and vascular permeability. We previously reported that some heavy metals interfere with proteoglycan expression, and that organic–inorganic hybrid molecules, such as metal complexes and organometallic compounds, serve as useful tools to analyze proteoglycan synthesis mechanisms. However, the effects of metal compounds lacking electrophilicity on proteoglycan synthesis remain unclear. Au₂₅(SG)₁₈, a nanoscale gold cluster consisting of a metal core protected by gold–glutathione complexes, exhibits extremely low intramolecular polarity. In this study, we investigated the effect of Au₂₅(SG)₁₈ on proteoglycan synthesis in vascular endothelial cells. Au₂₅(SG)₁₈ accumulated significantly in vascular endothelial cells at low cell density and suppressed the expression of perlecan, a major heparan sulfate proteoglycan in cells, by inactivating ADP-ribosylation factor 6 (Arf6). Additionally, Au₂₅(SG)₁₈ reduced the expression of biglycan, a small dermatan sulfate proteoglycan, in vascular endothelial cells at low cell density; however, the underlying mechanisms remain unclear. Overall, our findings suggest that organic–inorganic hybrid molecules regulate the activity of Arf6-mediated protein transport to the extracellular space and that perlecan is regulated through this mechanism, highlighting the importance of Arf6-mediated extracellular transport for maintaining vascular homeostasis. Full article

(This article belongs to the Special Issue Molecular Signaling and Mechanism on Vascular Remodeling)

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17 pages, 4374 KB

Open AccessArticle

Development of a Cellular Membrane Nanovesicle-Based Vaccine Against Porcine Epidemic Diarrhea Virus

by Xianjun Wang, Weibing Zhang, Hong Hu, Wenjing Gao, Xu Ma, Yarong Wu, Yongfeng Qiao, Yang Wang, Ding Zhang, Chunbo Dong, Haidong Wang and Zhida Liu

Cells 2026, 15(2), 208; https://doi.org/10.3390/cells15020208 - 22 Jan 2026

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Abstract

Porcine epidemic diarrhea virus (PEDV) has emerged as a major pathogen responsible for porcine diarrheal diseases, causing outbreaks of severe diarrhea and high mortality in neonatal piglets, thereby inflicting severe economic losses on the global swine industry. Current commercial PED vaccines, [...] Read more.

Porcine epidemic diarrhea virus (PEDV) has emerged as a major pathogen responsible for porcine diarrheal diseases, causing outbreaks of severe diarrhea and high mortality in neonatal piglets, thereby inflicting severe economic losses on the global swine industry. Current commercial PED vaccines, comprising conventional inactivated and live attenuated formulations, have exhibited progressively diminished efficacy in the face of emerging PEDV variants. The development of high-efficiency vaccine platforms is therefore critical for PED control. This study engineered a cellular membrane nanovesicle (CMN)-based vaccine, which differs from existing inactivated or subunit vaccines by presenting the PEDV spike (S) protein on the cell membranes to mimic the bilayer phospholipid structure of the viral envelope. The full-length S protein (FS, aa 19-1309) or a truncated S protein fragment (TS, aa 19-726) was expressed in Expi293F cells, followed by extraction of cell membranes to assemble antigen-displaying CMN vaccines. Compared with commercial live attenuated vaccine, administration of the CMN vaccine elicited high-titer neutralizing antibodies and elevated IFN-γ-producing CD8⁺ T cells in murine studies. Safety assessments revealed no adverse effects on body weight, hepatic/renal function indices, or histopathological parameters in vaccinated mice. Furthermore, immunization of piglets elicited notable humoral and CD8⁺ T cell immune responses. Collectively, the strategy of CMN-based vaccine described herein delivers a potential PEDV vaccine platform, thereby offering a novel avenue for next-generation veterinary vaccine development. Full article

(This article belongs to the Section Cellular Immunology)

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24 pages, 4581 KB

Open AccessArticle

The Taurine-Slc6a6 Axis Promotes Breast Cancer Progression by Alleviating Oxidative Stress and Accelerating Cell Cycle Progression

by Pei Cai, Xiaoqin Liu, Meizhen Lin, Shaofang Xie, Lei Yuan, Zuobao Lin, Yue Zhang and Shang Cai

Cells 2026, 15(2), 207; https://doi.org/10.3390/cells15020207 - 22 Jan 2026

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Abstract

Taurine metabolism is emerging as an important player in cancer progression, yet its precise roles remain incompletely understood. Our study revealed that elevated serum Taurine levels and concomitant upregulation of its transporter, Slc6a6, are associated with enhanced tumor growth. Functionally, Slc6a6 overexpression drives [...] Read more.

Taurine metabolism is emerging as an important player in cancer progression, yet its precise roles remain incompletely understood. Our study revealed that elevated serum Taurine levels and concomitant upregulation of its transporter, Slc6a6, are associated with enhanced tumor growth. Functionally, Slc6a6 overexpression drives tumor progression in vivo and accelerates cancer cell proliferation in vitro. Mechanistically, we identified a dual pro-oncogenic function for Slc6a6. First, Slc6a6 possesses intrinsic antioxidant regulatory capacity and further enhances cellular redox homeostasis by mediating the uptake of the antioxidant molecule Taurine. Second, beyond its metabolic role, Slc6a6 directly interacts with the cell cycle regulator Rprd1b to promote the G1/S phase transition, leading to uncontrolled proliferation. Clinically, bioinformatics analyses correlate high SLC6A6 expression with poor prognosis in breast cancer patients, underscoring its potential as a therapeutic target. Full article

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23 pages, 7890 KB

Open AccessArticle

Single-Cell Sequencing Reveals the Crosstalk Between MuSCs and FAPs in Ruminant Skeletal Muscle Development

by Yuan Chen, Yiming Gong, Xiaoli Xu, Meijun Song, Xueliang Sun, Jing Luo, Jiazhong Guo, Li Li and Hongping Zhang

Cells 2026, 15(2), 206; https://doi.org/10.3390/cells15020206 - 22 Jan 2026

Viewed by 222

Abstract

Skeletal muscle orchestrates a remarkable journey from embryonic formation to age-related decline, yet its cellular intricacies in goats remain largely uncharted. We present the first single-cell RNA sequencing (scRNA-seq) atlas of the longissimus dorsi muscle from goats, profiling 120,944 cells across 14 developmental [...] Read more.

Skeletal muscle orchestrates a remarkable journey from embryonic formation to age-related decline, yet its cellular intricacies in goats remain largely uncharted. We present the first single-cell RNA sequencing (scRNA-seq) atlas of the longissimus dorsi muscle from goats, profiling 120,944 cells across 14 developmental stages from embryonic day 30 (E30) to 11 years postnatal (Y11). We focused on skeletal muscle satellite cells (MuSCs) and fibro-adipogenic progenitors (FAPs), identifying a unique MuSCs_ACT1_high subpopulation in early embryogenesis and a senescence-associated MuSCs_CDKN1A_high subpopulation in later developmental stages. In FAPs, we characterized the early-stage FAPs_MDFI_high subpopulation with differentiation potential, which further exhibited the capacity to commit to both adipogenic and fibrogenic lineages. Transcription factor analysis revealed strikingly similar regulatory profiles between MuSCs and FAPs, suggesting that these two cell types are governed by shared signaling pathways during development. Cell–cell interaction analysis demonstrated that the DLK1-NOTCH3 ligand-receptor pair plays a critical role in enabling early embryonic FAPs to maintain the quiescent state of MuSCs. This dynamic single-cell transcriptomic atlas, spanning 14 developmental stages of skeletal muscle in ruminants for the first time, provides a valuable theoretical foundation for further elucidating the differentiation of skeletal muscle satellite cells and fibro-adipogenic progenitors in ruminants. Full article

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20 pages, 5380 KB

Open AccessArticle

Targeting SMPDL3B to Ameliorate Radiation- and Cisplatin-Induced Renal Toxicity

by Anis Ahmad, Shamroop Kumar Mallela, Saba Ansari, Mohammed Alnukhali, Sandra Merscher, Alla Mitrofanova, Youssef H. Zeidan, Alan Pollack, Alessia Fornoni and Brian Marples

Cells 2026, 15(2), 205; https://doi.org/10.3390/cells15020205 - 22 Jan 2026

Viewed by 197

Abstract

Kidney toxicity remains a major dose-limiting complication of radiation therapy and platinum-based chemotherapy, yet the molecular determinants of renal susceptibility and resilience to these genotoxic treatments are incompletely understood. Podocytes are particularly vulnerable to such insults, and emerging evidence implicates lipid dysregulation in [...] Read more.

Kidney toxicity remains a major dose-limiting complication of radiation therapy and platinum-based chemotherapy, yet the molecular determinants of renal susceptibility and resilience to these genotoxic treatments are incompletely understood. Podocytes are particularly vulnerable to such insults, and emerging evidence implicates lipid dysregulation in podocyte injury. This study investigated the role of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a podocyte-enriched lipid-modulating enzyme, in radiation- and cisplatin-induced nephrotoxicity. Using a doxycycline-inducible, podocyte-specific SMPDL3B transgenic mouse model, renal injury was assessed following focal kidney irradiation, cisplatin administration, or their combination through functional assays, histopathology, ultrastructural analysis, immunofluorescence, and targeted lipidomics. Combined radiation and cisplatin exposure markedly reduced podocyte SMPDL3B expression, accompanied by podocyte depletion, glomerular basement membrane remodeling, proteinuria, and impaired renal function. These structural and functional abnormalities were associated with the selective accumulation of long-chain ceramide-1-phosphate species. In contrast, podocyte-specific induction of SMPDL3B preserved glomerular architecture, maintained renal function, and prevented pathological ceramide-1-phosphate elevation. Collectively, these findings identify SMPDL3B as a key regulator of podocyte stability and lipid homeostasis during chemoradiation stress. Enhancing SMPDL3B activity may represent a mechanistically grounded strategy to mitigate treatment-induced kidney injury while preserving anticancer efficacy. Full article

(This article belongs to the Special Issue Cellular and Molecular Basis in Chronic Kidney Disease)

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17 pages, 3233 KB

Open AccessArticle

Neonatal Regulatory T Cells Mediate Fibrosis and Contribute to Cardiac Repair

by Tabito Kino, Sadia Mohsin, Yumi Chiba, Michiko Sugiyama and Tomoaki Ishigami

Cells 2026, 15(2), 204; https://doi.org/10.3390/cells15020204 - 22 Jan 2026

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Abstract

The neonatal heart possesses a unique capacity for reparative healing after myocardial injury, unlike the adult heart. While immune cells, particularly T cells, regulate post-infarction inflammation, their role in age-dependent cardiac repair remains unclear. This study aimed to characterize the temporal activation of [...] Read more.

The neonatal heart possesses a unique capacity for reparative healing after myocardial injury, unlike the adult heart. While immune cells, particularly T cells, regulate post-infarction inflammation, their role in age-dependent cardiac repair remains unclear. This study aimed to characterize the temporal activation of T cell subsets and their contribution to immune homeostasis and myocardial repair. Myocardial infarction was induced in mice of different ages, and T cell subsets (CD4+ T cells, CD8+ T cells, and CD4+Foxp3+ T [T-reg] cells) were analyzed using flow cytometry and RNA sequencing. Neonatal hearts exhibited CD4+ T cells, CD8+ T cells, and T-reg cells that gradually increased until seven days post-injury. Transcriptome analysis identified Rcn3 as a neonatal-specific, injury-responsive gene in T-reg cells, with minimal induction in adult and aged hearts, promoting a reparative microenvironment and exerting anti-fibrotic effects via the PI3K/Akt pathway. Under endoplasmic reticulum stress, Rcn3 activated unfolded protein response genes, and Rcn3-conditioned media reduced fibrosis-associated gene expression in adult cardiac fibroblasts. In a conditional knockout mouse model (Lck-cre; Rcn3^fl/fl), Rcn3 deletion in T cells led to impaired cardiac function recovery and increased fibrosis post-injury. These findings suggest that neonatal T-reg cells play a crucial role in cardiac repair, with Rcn3 as a potential therapeutic target for enhancing immune-mediated cardiac repair and limiting pathological remodeling in the adult heart. Full article

(This article belongs to the Special Issue Recent Progress on Fibrosis and Cardiac Dysfunction)

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25 pages, 1515 KB

Open AccessReview

Integrating GPCR Regulation and Calcium Dynamics in Airway Smooth Muscle Function: A Comprehensive Review

by Saptarshi Roy, Vijaya Kumar Gangipangi, Pravesh Sharma, Rebecca E. Hancock and Pawan Sharma

Cells 2026, 15(2), 203; https://doi.org/10.3390/cells15020203 - 21 Jan 2026

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Abstract

Asthma is a heterogeneous disease that varies in clinical presentation, severity, and underlying biology but consistently involves airway remodeling (AR) and airway hyperresponsiveness (AHR), which is characterized by excessive airway narrowing in response to various stimuli. Airway smooth muscle (ASM) cells are primary [...] Read more.

Asthma is a heterogeneous disease that varies in clinical presentation, severity, and underlying biology but consistently involves airway remodeling (AR) and airway hyperresponsiveness (AHR), which is characterized by excessive airway narrowing in response to various stimuli. Airway smooth muscle (ASM) cells are primary contributors to airway hyperresponsiveness and bronchoconstriction. This review focuses on ASM cells and their role in asthma. We discuss the mechanisms by which ASM mediates AHR, increases airway thickness, and contributes to AR. Signaling through G protein-coupled receptors (GPCRs) regulates many ASM functions, including contraction, growth, and the synthetic activities that drive airway inflammation and remodeling. GPCR-dependent calcium flux serves as a key signaling axis controlling the contractile responses of ASM. Here we provide a comprehensive summary of the major GPCRs as well as other non-GPCRs identified in ASM cells. GPCR-induced calcium mobilization, downstream signaling and how it has been linked to specific ASM functions are also discussed. Furthermore, we highlight the clinical significance of targeting GPCRs in asthma therapy as well as recent development of novel therapeutics in the management of asthma. Thus, this review provides a comprehensive overview of airway smooth muscle in the context of asthma pathophysiology. Full article

(This article belongs to the Section Cell Signaling)

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13 pages, 3528 KB

Open AccessArticle

A Human β-Defensin-Based Recombinant Protein DF₂-HSA Ameliorates Cytokine Storm

by Yibo Du, Zhuojun Yu, Weijin Sheng, Yi Li, Lei Hou, Yanbo Zheng, Xiujun Liu and Yongsu Zhen

Cells 2026, 15(2), 202; https://doi.org/10.3390/cells15020202 - 21 Jan 2026

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Abstract

Cytokine storm is a critical driver of acute respiratory distress syndrome and multiple organ failure. Human β-defensin 2 (HBD-2) is the first inducible defensin discovered in human body. Defensin can resist pathogenic microorganisms invading the body through direct bactericidal effect and also modulates [...] Read more.

Cytokine storm is a critical driver of acute respiratory distress syndrome and multiple organ failure. Human β-defensin 2 (HBD-2) is the first inducible defensin discovered in human body. Defensin can resist pathogenic microorganisms invading the body through direct bactericidal effect and also modulates acquired immune response. Albumin exhibits immunomodulatory properties and can reduce the level of inflammatory cytokines to improve the systemic inflammatory response. We previously engineered a recombinant fusion protein, DF₂-HSA, comprising two HBD-2 molecules linked to human serum albumin. Here, we evaluated its effect on cytokine storm using a lipopolysaccharide (LPS)-induced cytokine storm murine model (BALB/c athymic mice, female). DF₂-HSA reduced the mortality in cytokine storm murine model and prolonged the retention time of HBD-2 in the body. A Luminex assay showed that DF₂-HSA reduced the production of multiple inflammatory cytokines in cytokine storm murine model. Evans blue staining showed that DF₂-HSA reduced vascular leakage. Transmission electron microscopy showed that DF₂-HSA reduced the lung injury of cytokine storm mice. The pathological results showed that DF₂-HSA alleviated the lung and small intestine damage of cytokine storm mice. In summary, DF₂-HSA effectively inhibits cytokine storms and ameliorates associated tissue damage. Full article

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34 pages, 1354 KB

Open AccessReview

Dysregulation of Immune Mediators and Synaptic Plasticity in Central Nervous System Disorders

by Paola Imbriani, Clara D'Ambra, Roberta De Mori, Marta Ionta, Alessandro Renna and Paola Bonsi

Cells 2026, 15(2), 201; https://doi.org/10.3390/cells15020201 - 21 Jan 2026

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Abstract

Bidirectional communication between the central nervous system and the immune system is crucial for brain function, particularly in regulating neuroplasticity: on the one hand, glial cells modulate neuronal function, brain circuitry, axon myelination, dendritic spine architecture, and information processing, while on the other [...] Read more.

Bidirectional communication between the central nervous system and the immune system is crucial for brain function, particularly in regulating neuroplasticity: on the one hand, glial cells modulate neuronal function, brain circuitry, axon myelination, dendritic spine architecture, and information processing, while on the other hand, neuronal activity can alter the immune response. Neuroinflammation and dysregulation of astroglia and microglia can be detrimental to brain development and function. In particular, maladaptive responses and chronic glial activation have been correlated to synaptic dysfunction in diverse brain conditions. In the present review, we will provide a general introduction to the main players of the neuroimmune response and their ability to modulate neuroplasticity, followed by a comprehensive overview of experimental evidence linking the dysregulation of immune mediators to the disruption of synaptic plasticity in neurodegenerative and neurodevelopmental disorders, with a specific focus on Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder. Full article

(This article belongs to the Special Issue Synaptic Plasticity and the Neurobiology of Learning and Memory)

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3 pages, 146 KB

Open AccessEditorial

Editorial for the Special Issue “Glioblastoma: What Do We Know?”

by Shan Ping Yu

Cells 2026, 15(2), 200; https://doi.org/10.3390/cells15020200 - 21 Jan 2026

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Abstract

The Special Issue “Glioblastoma: What Do We Know [...] Full article

(This article belongs to the Special Issue Glioblastoma: What Do We Know?)

16 pages, 6305 KB

Open AccessArticle

Gne-Depletion in C2C12 Myoblasts Leads to Alterations in Glycosylation and Myopathogene Expression

by Carolin T. Neu, Aristotelis Antonopoulos, Anne Dell, Stuart M. Haslam and Rüdiger Horstkorte

Cells 2026, 15(2), 199; https://doi.org/10.3390/cells15020199 - 20 Jan 2026

Viewed by 856

Abstract

GNE myopathy is a rare genetic neuromuscular disorder caused by mutations in the GNE gene. The respective gene product, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), is a bifunctional enzyme that initiates endogenous sialic acid biosynthesis. Sialic acids are important building blocks [...] Read more.

GNE myopathy is a rare genetic neuromuscular disorder caused by mutations in the GNE gene. The respective gene product, UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE), is a bifunctional enzyme that initiates endogenous sialic acid biosynthesis. Sialic acids are important building blocks for the glycosylation machinery of cells and are typically found at the terminal ends of glycoprotein N- and O-glycans. The exact pathomechanism of GNE myopathy remains elusive, and a better understanding of the disease is urgently needed for the development of therapeutic strategies. The purpose of this study was to examine the effects of hyposialylation on glycan structures and subsequent downstream effects in the C2C12 Gne knockout cell model. No overall remodeling of N-glycans was observed in the absence of Gne, but differences in glycosaminoglycan expression and O-GlcNAcylation were detected. Expression analysis of myopathogenes revealed concomitant down-regulation of muscle-specific genes. Among the top candidates were the sodium channel protein type 4 subunit α (Scn4a), voltage-dependent L-type calcium channel subunit α-1s (Cacna1s), ryanodine receptor 1 (Ryr1), and glycogen phosphorylase (Pygm), which are associated with excitation-contraction coupling and energy metabolism. The results suggest that remodeling of the glycome could have detrimental effects on intracellular signaling, excitability of skeletal muscle tissue, and glucose metabolism. Full article

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18 pages, 4929 KB

Open AccessArticle

Integrative Epigenomic and Transcriptomic Profiling Define Malignancy- and Cluster-Specific Signatures in Pheochromocytomas and Paragangliomas

by Mouna Tabebi, Małgorzata Łysiak, Oliver Gimm and Peter Söderkvist

Cells 2026, 15(2), 198; https://doi.org/10.3390/cells15020198 - 20 Jan 2026

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Abstract

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors primarily involving the adrenal medulla and its associated paraganglia, with heterogeneous clinical behavior and complex molecular drivers. This study aimed to characterize DNA methylation and gene expression patterns in PPGLs to understand the molecular differences [...] Read more.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors primarily involving the adrenal medulla and its associated paraganglia, with heterogeneous clinical behavior and complex molecular drivers. This study aimed to characterize DNA methylation and gene expression patterns in PPGLs to understand the molecular differences between tumor subtypes and malignancy. We performed an integrative analysis of DNA methylation (Illumina EPIC 850K) and gene expression profiles (Affymetrix microarrays) in 24 PPGLs, comparing these with The Cancer Genome Atlas (TCGA) data, to delineate cluster- and malignancy-specific epigenetic patterns. Comparison between pseudohypoxic Cluster I and kinase-signaling Cluster II tumors revealed 13 differentially methylated CpG sites, with a specific CpG within DSCAML1 showing hypermethylation in Cluster II accompanied by increased expression, suggesting context-dependent gene body methylation effects. Benign versus malignant comparisons identified 101 differentially methylated CpGs, including hypermethylated CpG in BAIAP2L1 and hypomethylated CpG in SHANK1 in malignant tumors. Pathway enrichment of differentially methylated genes revealed alterations in Notch signaling, adherens junctions, cytoskeletal regulation, and intracellular transport. Gene expression analysis demonstrated partial overlap between clusters, with malignant tumors exhibiting distinct transcriptional profiles involving RNA processing, metabolism, and adhesion pathways. Correlation between methylation and expression was generally limited, emphasizing that methylation-dependent gene regulation is a locus-specific and context-dependent regulation. These findings illustrate a complex interplay between epigenetic modifications and transcriptional programs in PPGLs, enhancing our understanding of molecular heterogeneity and tumor classification, and identifying candidate biomarkers and therapeutic targets for malignant progression. Full article

(This article belongs to the Special Issue DNA Methylation in Human Health and Disease: From Molecular Mechanisms to Clinical Applications)

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23 pages, 639 KB

Open AccessReview

Synaptic Plasticity in Neurodegenerative Diseases: Impact of Exercise as Promising Therapeutic Tool

by Gabriele Farina, Gianmarco Fenili, Maria Paola Paronetto and Clara Crescioli

Cells 2026, 15(2), 197; https://doi.org/10.3390/cells15020197 - 20 Jan 2026

Viewed by 321

Abstract

Neurodegenerative diseases are distinguished by synaptic dysfunction and chronic neuroinflammation, which accelerate neuronal loss and impair network resilience. Synaptic plasticity, that is, the ability to adapt to changes, is progressively lost. This ability is part of hormesis, an adaptive biphasic response, nowadays acknowledged [...] Read more.

Neurodegenerative diseases are distinguished by synaptic dysfunction and chronic neuroinflammation, which accelerate neuronal loss and impair network resilience. Synaptic plasticity, that is, the ability to adapt to changes, is progressively lost. This ability is part of hormesis, an adaptive biphasic response, nowadays acknowledged as a promising tool in chronic degenerative diseases, since it offers a framework for personalized interventions. Growing evidence supports exercise as a powerful approach for managing neurodegenerative disorders, due to its capacity to enhance neuroplasticity through the direct targeting of the biomolecular processes involved. Indeed, regular exercise can drive many molecular mediators and signals toward neuroplasticity improvement, potentially slowing neurodegeneration. This narrative review focuses on exercise as a promising therapeutic approach in neurodegenerative diseases, based on its ability to shape synaptic plasticity at the molecular level. Some biomediators involved in synaptic plasticity function/dysfunction and neuroinflammation/neurodegeneration are addressed as therapeutic targets of exercise, and different exercise regimens are discussed as specific therapeutic interventions to contain the burden of some neurodegenerative conditions. Some clinical trials including exercise in the treatment of neurodegenerative diseases are summarized. Since no definitive disease-modifying cure exists for these illnesses, exercise’s ability to shape synaptic plasticity emerges as a highly attractive therapeutic approach. Full article

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

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27 pages, 8038 KB

Open AccessArticle

Effects of Repeated Intravenous Injections of Autologous Adipose-Derived Mesenchymal Stromal Cells Expressing an Allogeneic MHC Protein in a Mouse Model of Diabetic Nephropathy

by Fuxuan Li, Liangyu Zhao, Shengkun Wang, Ruixue Chen, Meiqi Meng, Yan Fu, Lin Wei, Wei Liu, Huixian Cui, Jun Ma, Matthew D. Griffin and Cuiqing Ma

Cells 2026, 15(2), 196; https://doi.org/10.3390/cells15020196 - 20 Jan 2026

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Abstract

Diabetic nephropathy (DN) is the most common cause of kidney failure worldwide. Mesenchymal stromal cells (MSCs) have demonstrated promise for treating DN by promoting kidney repair and regulating inflammation. Allogeneic (Allo)-MSCs may have similar or superior anti-inflammatory effects to autologous (Auto)-MSCs but also [...] Read more.

Diabetic nephropathy (DN) is the most common cause of kidney failure worldwide. Mesenchymal stromal cells (MSCs) have demonstrated promise for treating DN by promoting kidney repair and regulating inflammation. Allogeneic (Allo)-MSCs may have similar or superior anti-inflammatory effects to autologous (Auto)-MSCs but also have potential to elicit adverse immune responses due to major histocompatibility complex (MHC) mismatches. To better understand how MSC-delivered allo-antigens influence therapeutic effects of Allo-MSCs compared to Auto-MSCs in DN, lentiviral transduction was used to generate adipose-derived MSCs (ADSCs) from DBA/2J (H-2^d) mice which expressed an allogeneic class I MHC protein (H-2K^b). H-2K^b-ADSCs were injected intravenously into male DBA/2J mice at 11 and 13 weeks after initiation of diabetes, and their effects on renal functional and structural indices were compared at week 15 with those of diabetic DBA/2J recipients of vehicle alone or of empty vector-transduced DBA/2J ADSCs (EV-ADSCs). Both EV-ADSCs and H-2K^b-ADSCs resulted in reduced kidney/total body weight ratio, blood urea nitrogen (BUN), urine albumin creatinine ratio (uACR), mesangial matrix expansion (MME) and renal fibrosis compared to vehicle alone, without influencing glycemia or survival. However, H-2K^b-ADSCs recipients had greater reductions in BUN and uACR, reduced intra-renal myeloid cell infiltration, increased splenic regulatory T cell (Treg) proportions and increased intra-renal Treg infiltration and FOXP3 and IL-10 mRNA. Nonetheless, recipients of H-2K^b-ADSCs also had decreased splenic CD4/CD8 T cell ratios, increased circulating anti-H-2K^b IgG antibodies and histological and biochemical evidence of inflammatory liver injury. These novel findings demonstrated that ADSCs expressing an MHC-I allo-antigen had superior beneficial effects on DN than fully autologous ADSCs. Improved DN severity was associated with immune modulation, including Treg enhancement, but also had potentially detrimental immunological effects in mice with established diabetes. The results highlight the need for further investigation of the immune modulatory effects of Allo-MSCs in diabetes and its organ-specific complications. Full article

(This article belongs to the Special Issue Adipose-Derived Stem Cells: Current Applications and Future Directions)

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14 pages, 838 KB

Open AccessArticle

Reduced TIGIT Expression on T Cells Links Hyperglycemia to Immune Dysregulation in Type 1 Diabetes

by Martyna Tomaszewicz, Anna Ronowska, Julia Strzelecka, Agnieszka Jankowska-Kulawy, Katarzyna Stefańska, Piotr Trzonkowski and Maciej Zieliński

Cells 2026, 15(2), 195; https://doi.org/10.3390/cells15020195 - 20 Jan 2026

Viewed by 279

Abstract

T cells play an important role in the development and progression of type 1 diabetes (T1D). Checkpoint receptors regulate T cell activity, and their expression may be linked to the cells’ metabolic state. This study aims to investigate the association between T regulatory [...] Read more.

T cells play an important role in the development and progression of type 1 diabetes (T1D). Checkpoint receptors regulate T cell activity, and their expression may be linked to the cells’ metabolic state. This study aims to investigate the association between T regulatory (Treg) and T conventional (Tconv) cells expressing various checkpoint inhibitors and glucose metabolism in type 1 diabetes patients and healthy controls (HCs). The study included 28 participants, with 16 of them diagnosed with type 1 diabetes, while 12 constituted a healthy control group. Multicolor flow cytometry, spectrophotometric analysis, and bead-based multiplex assays were utilized for the analyses. The study revealed that the most significant difference in T cell subsets in peripheral blood concerned TIGIT. Compared to healthy subjects, the percentages of TIGIT+ Tregs and TIGIT+ Tconvs were lower in T1D patients. Interestingly, hyperglycemia in in vitro cultures reduced percentages of TIGIT+ Tregs and TIGIT+ Tconvs, and to some extent also CTLA-4+ Tregs. A decreased percentage of these subsets was, in turn, associated with reduced glucose uptake and lower activity of the enzymes responsible for various stages of glucose metabolism. The described associations suggest a negative influence of hyperglycemia in T1D on immune regulation via a TIGIT-dependent mechanism. Hyperglycemia seems to reduce the percentage of highly regulatory TIGIT+ Tregs both in vivo and in vitro, and it is associated with reduced glucose consumption by these cells. At the same time, a reduction in the percentage of TIGIT+ Tconvs under such conditions may facilitate higher activity of Tconvs, including aberrant autoimmune reactions. Full article

(This article belongs to the Section Cellular Metabolism)

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22 pages, 1511 KB

Open AccessReview

Ionic Mechanisms of Two-Pore Channel Regulation of Vesicle Trafficking

by Heng Zhang and Michael X. Zhu

Cells 2026, 15(2), 194; https://doi.org/10.3390/cells15020194 - 20 Jan 2026

Viewed by 247

Abstract

The endolysosomal system plays a pivotal role in cellular function. Before reaching lysosomes for degradation, the endocytosed cargoes are sorted at various stages of endosomal trafficking for recycling and/or rerouting. The proper execution of these processes depends on tightly regulated ion fluxes across [...] Read more.

The endolysosomal system plays a pivotal role in cellular function. Before reaching lysosomes for degradation, the endocytosed cargoes are sorted at various stages of endosomal trafficking for recycling and/or rerouting. The proper execution of these processes depends on tightly regulated ion fluxes across endolysosomal membranes. Recent studies have demonstrated the importance of two-pore channels (TPCs), including TPC1 and TPC2, in endolysosomal trafficking. These channels are expressed in the membranes of distinct populations of endosomes and lysosomes, where they respond to nicotinic acid adenine dinucleotide phosphate (NAADP) and phosphatidylinositol 3,5-bisphosphate [PI(3,5)P₂] to conduct Ca²⁺ and Na⁺ release from these acidic organelles. Here, we discuss the potential implications of Ca²⁺ and Na⁺ fluxes mediated by TPCs across endolysosomal membranes in the physiological and pathophysiological functions of these organellar channels. Full article

(This article belongs to the Special Issue Organellar Ca²⁺ Transport in Plant versus Animal Cells: Can We Learn from Each Other?)

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21 pages, 4845 KB

Open AccessArticle

Synchronizing the Liver Clock: Time-Restricted Feeding Aligns Rhythmic Gene Expression in Key Metabolic Pathways

by Shiyan Liu, Feng Zhang, Yiming Wang, Kailin Zhuo and Yingying Zhao

Cells 2026, 15(2), 193; https://doi.org/10.3390/cells15020193 - 20 Jan 2026

Viewed by 431

Abstract

Non-alcoholic fatty liver disease (NAFLD) is closely linked to metabolic syndrome and circadian rhythm disruption, yet the mechanisms by which lifestyle interventions restore circadian organization remain incompletely understood. In this study, we employed a stringent 3 h time-restricted feeding (TRF) regimen in a [...] Read more.

Non-alcoholic fatty liver disease (NAFLD) is closely linked to metabolic syndrome and circadian rhythm disruption, yet the mechanisms by which lifestyle interventions restore circadian organization remain incompletely understood. In this study, we employed a stringent 3 h time-restricted feeding (TRF) regimen in a mouse model of high-fat diet (HFD)-induced metabolic dysfunction. TRF markedly improved metabolic outcomes, including lipid accumulation, glucose tolerance, and behavioral and physiological rhythms. Importantly, through transcriptomic profiling using RNA sequencing, we found that TRF induced circadian rhythmicity in previously arrhythmic hepatic genes. This approach revealed that TRF promotes transcriptional synchronization within key metabolic pathways. Genes involved in autophagy, fatty acid metabolism, and protein catabolism exhibited coherent peak expression at defined time windows, suggesting that TRF temporally restructures gene networks to enhance metabolic efficiency. This intra-pathway synchronization likely minimizes energy waste and enables cells to execute specialized functions in a temporally optimized manner. Together, our findings identify temporal reorganization of metabolic pathways as a mechanistic basis for the benefits of TRF, providing new insight into circadian-based strategies for managing metabolic disease. Full article

(This article belongs to the Special Issue Circadian Rhythms in Action: Cellular and Molecular Mechanisms Revealed by Model Organisms)

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14 pages, 3029 KB

Open AccessArticle

TRPA1 as a Key Regulator of Keratinocyte Homeostasis and Inflammation in Human Skin

by Caterina Cattani, Claudia Scarponi, Martina Morelli, Kilian Eyerich, Stefanie Eyerich, Christian Napoli, Stefania Madonna, Cristina Albanesi, Andrea Cavani and Fernanda Scopelliti

Cells 2026, 15(2), 192; https://doi.org/10.3390/cells15020192 - 20 Jan 2026

Viewed by 276

Abstract

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is a non-selective cation channel activated by a range of physical and chemical stimuli. While primarily studied in neuronal tissues, TRPA1 is also expressed in human keratinocytes, where its role remains poorly understood. Here, we [...] Read more.

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel is a non-selective cation channel activated by a range of physical and chemical stimuli. While primarily studied in neuronal tissues, TRPA1 is also expressed in human keratinocytes, where its role remains poorly understood. Here, we investigated TRPA1 expression and function in keratinocytes and examined the effects of its activation on cellular proliferation, immune activation, and neuropeptide release under both basal and inflammatory stimuli. TRPA1 expression was detected in basal keratinocytes and was upregulated by pro-inflammatory cytokines. Stimulation with the TRPA1 agonist allyl isothiocyanate (AITC) induced a rapid calcium influx, confirming functional channel activity. AITC at 5 µM did not induce cytotoxicity but significantly reduced keratinocyte proliferation and caused cell cycle arrest. Under stimulation with TNF-α and IFN-γ, TRPA1 activation decreased the surface expression of HLA-DR and ICAM-1, and downregulated mRNA levels of CXCL10, CXCL8, CCL5, and CCL20, while IL-6 expression remained unchanged. Furthermore, AITC treatment reduced the secretion of Substance P, but not CGRP. These findings indicate that TRPA1 functions as a cytokine-inducible, immunomodulatory receptor in human keratinocytes, capable of attenuating proliferation and inflammatory activation without compromising cell viability, thereby suggesting a potential role in maintaining skin homeostasis and modulating cutaneous inflammation. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels and Health and Disease)

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30 pages, 1304 KB

Open AccessReview

Stem Cell-Derived Beta-Cell Therapies: Encapsulation Advances and Immunological Hurdles in Diabetes Treatment

by Sana Waris, Hamna Hameetha Begam, Manyam Praveen Kumar, Zahra Husain I. Abdulrasool, Muthulakshmi Avudaiappan, Alexandra E. Butler and Manjula Nandakumar

Cells 2026, 15(2), 191; https://doi.org/10.3390/cells15020191 - 20 Jan 2026

Cited by 1 | Viewed by 885

Abstract

Diabetes mellitus encompasses a heterogeneous group of metabolic disorders defined by abnormalities in insulin secretion, function, or both. Exogenous insulin therapy has long been the principal treatment strategy for patients with type 1 diabetes and for those in advanced stages of type 2 [...] Read more.

Diabetes mellitus encompasses a heterogeneous group of metabolic disorders defined by abnormalities in insulin secretion, function, or both. Exogenous insulin therapy has long been the principal treatment strategy for patients with type 1 diabetes and for those in advanced stages of type 2 diabetes. Stem cell therapy has gained significant attention in recent years as a potential curative approach for several life-threatening disorders. In this review, we focus on the use of induced pluripotent stem cells as an alternative source for beta-cell generation, offering a solution to organ scarcity and providing a sustainable supply of insulin-producing cells. We further evaluate current developments in encapsulation technologies and transplantation sites, while noting that the issue of immune-mediated graft rejection continues to be widely debated. The aim of this review is to outline encapsulation techniques and transplantation approaches explored in animal models, and to discuss the risks and challenges anticipated in human clinical trials. Full article

(This article belongs to the Special Issue Advancements in Research on hiPSC-Derived Cells)

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23 pages, 2194 KB

Open AccessArticle

Unraveling the Impact of KRAS Accessory Proteins on Oncogenic Signaling Pathways

by Vanshika Garg, Raphael N. H. M. Hofmann, Moazzam Saleem, Amin Mirzaiebadizi, Ghazaleh Sadat Hashemi, Tooba Hameed, Bahareh Jooyeh, Silke Pudewell, Mehrnaz Mehrabipour, Niloufar Mosaddeghzadeh, Roland P. Piekorz and Mohammad Reza Ahmadian

Cells 2026, 15(2), 190; https://doi.org/10.3390/cells15020190 - 20 Jan 2026

Viewed by 533

Abstract

The oncogene KRAS drives tumor growth by activating pathways such as MAPK and PI3K-AKT in a constitutive manner. Although direct KRAS inhibitors exist, they are often limited in clinical use due to therapeutic resistance and toxicity. Therefore, alternative combinatorial therapeutic strategies are urgently [...] Read more.

The oncogene KRAS drives tumor growth by activating pathways such as MAPK and PI3K-AKT in a constitutive manner. Although direct KRAS inhibitors exist, they are often limited in clinical use due to therapeutic resistance and toxicity. Therefore, alternative combinatorial therapeutic strategies are urgently needed. This study examined the knockout of five KRAS-related proteins—galectin-3 (GAL3), phosphodiesterase delta (PDEδ), nucleophosmin (NPM1), IQ motif-containing GTPase-activating protein 1 (IQGAP1), and SHOC2—using CRISPR-Cas9 in adenocarcinoma cell lines harboring the KRAS(G12V) oncogenic mutation, as well as in the noncancerous HEK-293 cell line. These proteins act as critical modulators that regulate KRAS activity, cellular localization, and that of its downstream signaling components. We analyzed the downstream activation of ERK and AKT kinases and evaluated subsequent cancer cell proliferation. Knockout of GAL3 and PDEδ was highly effective, significantly reducing MAPK and PI3K-AKT pathway activity and substantially impairing cell proliferation. SHOC2 knockout selectively and potently disrupted MAPK activation, while NPM1 knockout resulted in the complex, reciprocal modulation of the two major pathways. Notably, knocking out IQGAP1 enhanced PI3K–AKT and mTORC2–AKT signaling without affecting the MAPK pathway. These distinct modulatory roles highlight the non-redundant functions of the accessory proteins. In conclusion, our findings establish GAL3 and PDEδ, two KRAS-associated proteins, as promising combinatorial drug targets. Targeting these modulators provides an effective alternative strategy to overcome resistance mechanisms and enhance the clinical utility of existing KRAS inhibitors. Full article

(This article belongs to the Special Issue Ras Family of Genes and Proteins: Structure, Function and Regulation)

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21 pages, 4059 KB

Open AccessArticle

Human Dental Pulp Stem Cells Modulate Acute Inflammation Kinetics in the AIRmax Murine Model by Sustained TNF-Alpha Suppression and Transient Homing

by Bruna de Oliveira Policiquio, Vivian Gonzaga Fonseca, Geovanna Santos Costa, Jean Gabriel de Souza, Olga Celia Martinez Ibañez, Orlando Garcia Ribeiro and Irina Kerkis

Cells 2026, 15(2), 189; https://doi.org/10.3390/cells15020189 - 20 Jan 2026

Viewed by 190

Abstract

Mesenchymal stem cells (MSCs) are multipotent adult cells that are highly valued for their immunomodulatory potential and intrinsic ability to home to inflamed sites. This study specifically utilized human dental pulp stem cells (hDPSCs), a unique MSC subtype derived from the neural crest, [...] Read more.

Mesenchymal stem cells (MSCs) are multipotent adult cells that are highly valued for their immunomodulatory potential and intrinsic ability to home to inflamed sites. This study specifically utilized human dental pulp stem cells (hDPSCs), a unique MSC subtype derived from the neural crest, due to their reported superior anti-inflammatory capacity. To rigorously test their efficacy, we employed the AIRmax murine model, which exhibits a genetically determined high-inflammatory phenotype. Acute inflammation was induced by subcutaneous injection of the polyacrylamide suspension Biogel P-100. Two hours post-induction, AIRmax mice were treated intravenously with hDPSCs. Our results demonstrate that hDPSC treatment produced significant anti-inflammatory effects evident at 24 h. The treated group showed a pronounced reduction in leukocyte migration and decreased protein extravasation in the inflammatory exudate. Crucially, hDPSCs also modulated molecular mediators, significantly decreasing the pro-inflammatory cytokine TNF-alpha and reactive oxygen species (ROS) production. Furthermore, while hDPSCs efficiently and rapidly homed to the inflammation site within 2 h, their maximal therapeutic benefits only manifested after 24 h. This suggests that their robust capacity to modulate acute inflammatory responses relies not only on rapid migration but also on a paracrine “hit-and-run” mechanism that suppresses cellular infiltration and oxidative stress over time. This study reinforces the potential of hDPSCs as a powerful, multi-target therapeutic agent for inflammatory conditions, supporting further investigation into their precise mechanisms and clinical application. Full article

(This article belongs to the Special Issue Immunoregulatory Functions of Mesenchymal Stem Cells (MSCs))

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27 pages, 1530 KB

Open AccessReview

Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins

by Pauline Adjibade and Rachid Mazroui

Cells 2026, 15(2), 188; https://doi.org/10.3390/cells15020188 - 20 Jan 2026

Viewed by 432

Abstract

Cells are continuously exposed to physiological and environmental stressors that disrupt homeostasis, triggering adaptive mechanisms such as the integrated stress response (ISR). A central feature of ISR is the selective translation of activating transcription factor 4 (ATF4), which orchestrates gene programs essential for [...] Read more.

Cells are continuously exposed to physiological and environmental stressors that disrupt homeostasis, triggering adaptive mechanisms such as the integrated stress response (ISR). A central feature of ISR is the selective translation of activating transcription factor 4 (ATF4), which orchestrates gene programs essential for metabolic adaptation and survival. Stress-induced acute ATF4 expression occurs in diverse mammalian cell types and is typically protective; however, chronic activation contributes to pathologies including cancer and neurodegeneration. Canonical ISR (c-ISR) is initiated by phosphorylation of eIF2α in response to stressors such as endoplasmic reticulum or mitochondrial dysfunction, hypoxia, nutrient deprivation, and infections. This modification suppresses global protein synthesis while promoting ATF4 translation through upstream open reading frames (uORFs) in its 5′UTR. Recently, an alternative pathway, split ISR (s-ISR), enabling ATF4 translation independently of eIF2α phosphorylation, was identified in mice, suggesting ISR adaptability, though its relevance in humans remains unclear. Under normal conditions, cap-dependent translation predominates, mediated by the eIF4F complex and requiring the activity of eIF2B at its initial steps. During translational stress, eIF2α phosphorylation inhibits eIF2B activity, resulting in the formation of stalled initiation complexes, which can aggregate into stress granules (SGs). SGs sequester mRNAs and translation initiation factors, further repressing global translation, while ATF4 mRNA largely escapes sequestration, enabling selective translation. This partitioning highlights a finely tuned regulatory mechanism balancing ATF4 expression during stress. Recent advances reveal that, beyond cis-regulatory uORFs, trans-acting factors such as translation initiation factors and associated RNA-binding proteins critically influence ATF4 translation. Understanding these mechanisms provides insight into ISR plasticity and its implications for development, aging, and disease. Full article

(This article belongs to the Special Issue Protein and RNA Regulation in Cells)

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33 pages, 1729 KB

Open AccessReview

Versatile hiPSC Models and Bioengineering Platforms for Investigation of Atrial Fibrosis and Fibrillation

by Behnam Panahi, Saif Dababneh, Saba Fadaei, Hosna Babini, Sanjana Singh, Maksymilian Prondzynski, Mohsen Akbari, Peter H. Backx, Jason G. Andrade, Robert A. Rose and Glen F. Tibbits

Cells 2026, 15(2), 187; https://doi.org/10.3390/cells15020187 - 20 Jan 2026

Viewed by 513

Abstract

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder. It is estimated that AF affects over 52 million people worldwide, with its prevalence expected to double in the next four decades. AF significantly increases the risk of stroke and heart failure, [...] Read more.

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder. It is estimated that AF affects over 52 million people worldwide, with its prevalence expected to double in the next four decades. AF significantly increases the risk of stroke and heart failure, contributing to 340,000 excess deaths annually. Beyond these life-threatening complications, AF results in limitations in physical, emotional, and social well-being causing significant reductions in quality of life and resulting in 8.4 million disability-adjusted life-years per year, highlighting the wide-ranging impact of AF on public health. Moreover, AF is increasingly recognized for its association with cognitive decline and dementia. AF is a chronic and progressive disease characterized by rapid and erratic electrical activity in the atria, often in association with structural changes in the heart tissue. AF is often initiated by triggered activity, often from ectopic foci in the pulmonary veins. These triggered impulses may initiate AF via: (1) sustained rapid firing with secondary disorganization into fibrillatory waves, or (2) by triggering micro re-entrant circuits around the pulmonary venous-LA junction and within the atrial body. In each instance, AF perpetuation necessitates the presence of a vulnerable atrial substrate, which perpetuates and stabilizes re-entrant circuits through a combination of slowed and heterogeneous conduction, as well as functional conduction abnormalities (e.g., fibrosis disrupting tissue integrity, and abnormalities in the intercalated disks disrupting effective cell-to-cell coupling). The re-entry wavelength, determined by conduction velocity and refractory period, is shortened by slowed conduction, favoring AF maintenance. One major factor contributing to these changes is the disruption of the extracellular matrix (ECM), which is induced by atrial fibrosis. Fibrosis-driven disruption of the ECM, especially in the heart and blood vessels, is commonly caused by conditions such as aging, hypertension, diabetes, smoking, and chronic inflammatory or autoimmune diseases. These factors lead to excessive collagen and protein deposition by activated fibroblasts (i.e., myofibroblasts), resulting in increased tissue stiffness, maladaptive remodeling, and impaired organ function. Fibrosis typically occurs when cardiac fibroblasts are activated to myofibroblasts, resulting in the deposition of excessive collagen and other proteins. This change in ECM interferes with the normal electrical function of the heart by creating irregular, fibrotic regions. AF and atrial fibrosis have a reciprocal relationship: AF promotes fibrosis through fibroblast activation and extracellular matrix buildup, while atrial fibrosis can sustain and perpetuate AF, contributing to higher rates of AF recurrence after treatments such as catheter ablation or cardioversion. Full article

(This article belongs to the Special Issue The Roles of the Extracellular Matrix in Cardiac Structure and Function: A Commemorative Issue in Honor of Dr. Thomas K. Borg)

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15 pages, 2218 KB

Open AccessArticle

Zinc Permeation Through Acid-Sensing Ion Channels

by Xiang-Ping Chu, Koichi Inoue and Zhi-Gang Xiong

Cells 2026, 15(2), 186; https://doi.org/10.3390/cells15020186 - 20 Jan 2026

Viewed by 298

Abstract

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by [...] Read more.

Acid-sensing ion channels (ASICs), activated under acidic conditions, play a critical role in ischemic brain injury, but the detailed mechanisms and signaling pathways remain unclear. Our previous studies have shown that activation of ASIC1a channels contributes to acidosis-induced neuronal injury, partially mediated by increased calcium influx. In this study, we provide evidence that activation of ASIC2a-containing channels induces zinc influx. In cultured mouse cortical neurons, ASIC currents that were insensitive to PcTx1 inhibition were potentiated by extracellular zinc. In Chinese Hamster Ovary cells transfected with different ASIC subunits, large inward currents were recorded upon a pH drop from 7.4 to 5.0 in cells expressing homomeric ASIC1a, ASIC2a, or heteromeric ASIC1a/2a channels when normal Na⁺-rich extracellular fluid (ECF) was used. However, when ECF was modified to one containing zinc as the primary cation, the same pH drop induced an inward current only in cells expressing homomeric ASIC2a or heteromeric ASIC1a/2a, but not homomeric ASIC1a. Fluorescence imaging revealed rapid zinc influx in cells expressing ASIC2a but not ASIC1a when zinc was applied with the acidic ECF. Additionally, at pH values where ASIC2a-containing channels were activated, acid-mediated neurotoxicity was exacerbated by zinc. Thus, ASIC2a-containing channels may represent a novel pathway for zinc entry and activation of these channels might contribute to zinc-mediated neurotoxicity. Full article

(This article belongs to the Special Issue pH Sensing, Signalling, and Regulation in Cellular Processes )

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41 pages, 3913 KB

Open AccessReview

Advancing Bioconjugated Quantum Dots with Click Chemistry and Artificial Intelligence to Image and Treat Glioblastoma

by Pranav Kalaga and Swapan K. Ray

Cells 2026, 15(2), 185; https://doi.org/10.3390/cells15020185 - 19 Jan 2026

Viewed by 578

Abstract

Glioblastoma (GB) is one of the most aggressive and invasive cancers. Current treatment protocols for GB include surgical resection, radiotherapy, and chemotherapy with temozolomide. However, despite these treatments, physicians still struggle to effectively image, diagnose, and treat GB. As such, patients frequently experience [...] Read more.

Glioblastoma (GB) is one of the most aggressive and invasive cancers. Current treatment protocols for GB include surgical resection, radiotherapy, and chemotherapy with temozolomide. However, despite these treatments, physicians still struggle to effectively image, diagnose, and treat GB. As such, patients frequently experience recurrence of GB, demanding innovative strategies for early detection and effective therapy. Bioconjugated quantum dots (QDs) have emerged as powerful nanoplatforms for precision imaging and targeted drug delivery due to their unique optical properties, tunable size, and surface versatility. Due to their extremely small size, QDs can cross the blood–brain barrier and be used for precision imaging of GB. This review explores the integration of QDs with click chemistry for robust bioconjugation, focusing on artificial intelligence (AI) to advance GB therapy, mechanistic insights into cellular uptake and signaling, and strategies for mitigating toxicity. Click chemistry enables site-specific and stable conjugation of targeting ligands, peptides, and therapeutic agents to QDs, enhancing selectivity and functionalization. Algorithms driven by AI may facilitate predictive modeling, image reconstruction, and personalized treatment planning, optimizing QD design and therapeutic outcomes. We discuss molecular mechanisms underlying interactions of QDs with GB, including receptor-mediated endocytosis and intracellular trafficking, which influence biodistribution and therapeutic efficacy. Use of QDs in photodynamic therapy, which uses reactive oxygen species to induce apoptotic cell death in GB cells, is an innovative therapy that is covered in this review. Finally, this review addresses concerns associated with the toxicity of metal-based QDs and highlights how QDs can be coupled with AI to develop new methods for precision imaging for detecting and treating GB for induction of apoptosis. By converging nanotechnology and computational intelligence, bioconjugated QDs represent a transformative platform for paving a safer path to smarter and more effective clinical interventions of GB. Full article

(This article belongs to the Special Issue Cell Death Mechanisms and Therapeutic Opportunities in Glioblastoma)

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41 pages, 13009 KB

Open AccessArticle

Comparative Profiling of Mouse and Human Microglial Small Extracellular Vesicles Reveals Conserved Core Functions with Distinct miRNA Signatures

by Amir-Hossein Bayat, Damien D. Pearse, Praveen Kumar Singh and Mousumi Ghosh

Cells 2026, 15(2), 184; https://doi.org/10.3390/cells15020184 - 19 Jan 2026

Viewed by 301

Abstract

Microglia-derived small extracellular vesicles (MGEVs) are key mediators of neuroimmune communication, yet their cross-species comparability and translational relevance remain poorly defined. Here, we establish a harmonized framework to compare the molecular and biochemical signatures of sEVs derived from immortalized mouse (BV2) and human [...] Read more.

Microglia-derived small extracellular vesicles (MGEVs) are key mediators of neuroimmune communication, yet their cross-species comparability and translational relevance remain poorly defined. Here, we establish a harmonized framework to compare the molecular and biochemical signatures of sEVs derived from immortalized mouse (BV2) and human (HMC3) microglial cells as well as assess their bioactivity on a human Schwann cell (HuSC) line. MGEVs were isolated via MISEV-aligned size-exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), and immunoblotting for canonical EV markers CD9, CD63, CD81, TSG101. Human and mouse MGEVs exhibited similar morphology but displayed distinct membrane tetraspanin protein enrichment patterns. Functionally, mouse and human MGEVs attenuated HuSC migration while enhancing HuSC proliferation and their resistance to H₂O₂-induced oxidative stress, with human MGEVs providing stronger protective effects, suggesting they retain similar core functional properties. Short, non-coding-miRNA sequencing analysis identified 196 shared miRNAs (Spearman ρ = 0.72) with species-specific enrichment: human MGEVs-derived miRNAs favored regenerative and metabolic pathways, whereas mouse MGEVs-derived miRNAs aligned more so with inflammatory signaling. This study delivers the first integrated cross-species blueprint of MGEVs, revealing conserved neuroprotective actions alongside species-biased miRNA cargo that define translational boundaries and highlight human-relevant MGEV signatures for therapeutic innovation, therefore contributing to the importance of considering these differences in translational research. Full article

(This article belongs to the Special Issue Beyond Bystanders: The Emerging Roles of Glia in Brain Health and Disease)

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16 pages, 1227 KB

Open AccessArticle

PD-L1 and BAP1 as Prognostic Biomarkers in Malignant Pleural Mesothelioma

by Milija Gajić, Vesna Ćeriman Krstić, Natalija Samardžić, Ivan Soldatović, Sofija Glumac, Milena Jovanović, Milan Savić, Mihailo Stjepanović, Spasoje Popević, Ruža Stević, Nikola Čolić, Katarina Lukić, Vladimir Milenković, Ivan Milivojević, Ivana Sekulović Radovanović and Dragana Jovanović

Cells 2026, 15(2), 183; https://doi.org/10.3390/cells15020183 - 19 Jan 2026

Viewed by 278

Abstract

Malignant pleural mesothelioma (MPM) is a very aggressive tumor. The prognostic value of PD-L1 and BAP1 expression has been investigated in many studies. A retrospective study was conducted that analyzed PD-L1 and BAP1 expression as prognostic biomarkers in patients with MPM. The study [...] Read more.

Malignant pleural mesothelioma (MPM) is a very aggressive tumor. The prognostic value of PD-L1 and BAP1 expression has been investigated in many studies. A retrospective study was conducted that analyzed PD-L1 and BAP1 expression as prognostic biomarkers in patients with MPM. The study included 53 patients with MPM. PD-L1 expression ≥ 1% was found in 39.6%, and BAP1 loss was found in 81.1% of patients. The median overall survival (mOS) was 11 months. Subtype of MPM (p = 0.045), early tumor stage (p = 0.049), therapy (p = 0.002), and good PS (0–1) (p = 0.012) were associated with better survival. Expression of PD-L1 and BAP1 did not show statistical significance regarding OS, but OS was numerically shorter in patients with PD-L1 ≥ 10% (5 vs. 12 months) and longer in patients with BAP1 loss (12 vs. 4 months). In patients with PD-L1 ≥ 1% and BAP1 loss, the median progression-free survival (mPFS) was numerically longer (10 vs. 7 months) but in patients with PD-L1 ≥ 1% and BAP1 positivity, PFS was statistically significantly shorter (1 vs. 7 months, p = 0.048). Our results did not show that PD-L1 and BAP1 are prognostic biomarkers for MPM, but positive PD-L1 expression and BAP1 loss were associated with worse survival in patients with MPM. Full article

(This article belongs to the Special Issue Thoracic Tumors: Decoding Cellular Heterogeneity, Tumor Microenvironment Crosstalk, and Therapeutic Vulnerabilities)

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18 pages, 6060 KB

Open AccessArticle

Cerebellar Resistance to Amyloid Plaque Deposition and Elevated Microglial ECM Proteoglycan Uptake in 5xFAD Mice

by Carla Cangalaya, Henning Peter Düsedau, Ildiko Rita Dunay, Alexander Dityatev and Stoyan Stoyanov

Cells 2026, 15(2), 182; https://doi.org/10.3390/cells15020182 - 19 Jan 2026

Viewed by 419

Abstract

In both Alzheimer’s disease (AD) patients and animal models, senile plaques are generally observed in the cerebral cortex rather than the cerebellum. The mechanisms underlying the regional resistance of the cerebellum to amyloid plaque deposition remain poorly understood. We investigated this cerebellar resistance [...] Read more.

In both Alzheimer’s disease (AD) patients and animal models, senile plaques are generally observed in the cerebral cortex rather than the cerebellum. The mechanisms underlying the regional resistance of the cerebellum to amyloid plaque deposition remain poorly understood. We investigated this cerebellar resistance using 5xFAD mice, an amyloidosis model with high expression of mutant human APP and PSEN1 in the cortex and cerebellum. In aged 5xFAD mice, the cerebellum had minimal amyloid-β (Aβ) deposition despite robust transgene expression, correlating with lower expression levels of IBA1, CD68, TREM2, and CD36 (although elevated expression of CD45 and MHC I) compared to the cortex. Consistent with the absence of plaques, cerebellar tissue lacked the dystrophic VGLUT1-positive synaptic accumulations prominent in the cortex. Cerebellar microglia maintained a distinct, less inflammatory phenotype yet displayed efficient clearance activity. Notably, ASC inflammasome specks—capable of seeding Aβ aggregation—were paradoxically more abundant in the cerebellum, implying that rapid Aβ clearance prevents these seeds from driving plaque formation. Furthermore, key extracellular matrix (ECM) proteoglycans brevican and aggrecan were elevated in the 5xFAD cerebellum. Cerebellar microglia showed enhanced internalization of brevican alongside small Aβ aggregates, exceeding that in cortical microglia. These findings indicate that region-specific microglial and ECM interactions—particularly efficient uptake and degradation of ECM–Aβ co-aggregates—may underlie the cerebellum’s resilience to amyloid plaque pathology. Full article

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

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