Cells

28 pages, 5416 KB

Open AccessArticle

Effects of α-Synuclein on the Lipid Phenotype of SZ95 Human Sebocytes: A Preliminary Study in the Context of Parkinson’s Disease

by Sarah Mosca, Grazia Bottillo, Enrica Flori, Daniela Kovacs, Miriam Maiellaro, Francesca Lozzi, Alessia Cavallo, Christos C. Zouboulis, Giulia Simmini, Alessia Luppino, Claudia Novello, Valentina Leta, Gianfranco Gaudiano, Grazia Devigili, Roberto Eleopra, Fabrizio Tagliavini, Samanta Mazzetti, Emanuela Camera and Giorgia Cardinali

Cells 2026, 15(16), 1505; https://doi.org/10.3390/cells15161505 - 21 Aug 2026

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Abstract

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis [...] Read more.

Pathological aggregation of α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD), but increasing evidence indicates that αSyn deposits extend beyond the central nervous system to peripheral tissues, including the skin. In PD patients, cutaneous αSyn accumulation has been associated with seborrheic dermatitis (SD), a chronic inflammatory condition linked to sebocyte dysfunction and altered sebum production. Marked differences in sebum composition between PD patients and healthy controls have been described. We aimed to investigate whether pathological αSyn could contribute to dysregulated sebum production and composition by assessing key markers of sebocyte differentiation and lipogenesis in human sebaceous gland cells and skin biopsies from PD patients (n = 5) and matched controls (n = 5) without clinically recorded SD. O-αSyn exposure of immortalized sebaceous gland cells (SZ95) altered the transcriptional programs related to sebocyte differentiation, inflammation, metabolism, and lipogenesis. Consistently, protein markers of mid-to-late sebocyte differentiation were increased. Upregulation of PLIN2, together with elevated PPARγ, SREBP1, SCD1, and FADS2, indicated progression toward a mature and lipid-producing phenotype characterized by enhanced accumulation of neutral lipids within lipid droplets. Lipidomic profiling revealed remodeling of multiple lipid classes, with increases in triglycerides, ceramides, and selected phospholipids. Increased expression of PLIN2 and PPARγ was also observed in sebaceous glands from PD skin biopsies compared to controls. Collectively, our findings indicate that O-αSyn exposure is associated with molecular changes consistent with altered sebocyte differentiation and lipid remodeling. These results support a potential association between αSyn and lipid dysregulation in sebocytes and suggest that these cells may represent unrecognized peripheral targets of αSyn. Full article

(This article belongs to the Special Issue Turning Points in α-Synuclein Biology: From Function to Dysfunction)

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18 pages, 5601 KB

Open AccessArticle

Effects of Wharton’s Jelly Mesenchymal Stem Cell-Derived Secretome on Cell Functions in Human Endometrium

by Silviya Doneva, Kalina Belemezova, Vesela Stoycheva, Ivan Bochev, Tanya Timeva, Maria Yunakova, Petya Andreeva, Katerina Kavaldzhieva, Atanas Shterev and Stanimir Kyurkchiev

Cells 2026, 15(16), 1504; https://doi.org/10.3390/cells15161504 - 21 Aug 2026

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Abstract

Background: Thin endometrium is a significant cause of infertility due to impaired regeneration, reduced receptivity, and insufficient angiogenesis. Mesenchymal stem cell-derived secretome (MSCsec) is a promising cell-free therapy because it contains bioactive molecules that promote tissue repair. This study evaluated the effects of [...] Read more.

Background: Thin endometrium is a significant cause of infertility due to impaired regeneration, reduced receptivity, and insufficient angiogenesis. Mesenchymal stem cell-derived secretome (MSCsec) is a promising cell-free therapy because it contains bioactive molecules that promote tissue repair. This study evaluated the effects of Wharton’s jelly-derived MSC secretome (WJ-MSCsec) on human endometrial stromal cells (EnSCs) and endothelial cells in vitro. Methods: WJ-MSCs were isolated from umbilical cord tissue, characterized, and cultured under serum-free conditions. The concentrated secretome was analyzed using a human angiogenesis proteome array. EnSCs were isolated from endometrial biopsies. EnSC proliferation and migration in the presence of WJ-MSCsec were assessed using CCK-8 and scratch wound-healing assays. Pro-angiogenic activity of WJ-MSCsec was evaluated using a Matrigel tube formation assay with human umbilical vein endothelial cells (HUVECs). Results: Proteomic analysis of WJ-MSCsec revealed the presence of angiogenic, mitogenic, immunomodulatory, and chemotactic factors. Treatment with WJ-MSCsec significantly enhanced EnSC proliferation and accelerated wound closure. Furthermore, WJ-MSCsec markedly promoted endothelial tube formation, increasing total tube length, junction number, and mesh formation. Conclusions: WJ-MSCsec stimulates EnSC proliferation and migration while enhancing angiogenesis in vitro. WJ-MSCsec represents a promising cell-free therapeutic strategy for endometrial regeneration and reproductive disorders associated with impaired endometrial function. Full article

(This article belongs to the Section Stem Cells)

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38 pages, 3144 KB

Open AccessReview

AMPK Therapy—A Little Goes A Long Way

by Hannah Ceballos, Eryun Zhang and Wendong Huang

Cells 2026, 15(16), 1503; https://doi.org/10.3390/cells15161503 - 20 Aug 2026

Viewed by 698

Abstract

AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that integrates energetic, nutrient, hormonal, redox, and stress signals to coordinate cellular and whole-body energy homeostasis. Although AMPK was initially characterized primarily as a sensor of changes in cellular AMP/ATP ratios, recent studies [...] Read more.

AMP-activated protein kinase (AMPK) is a highly conserved serine/threonine kinase that integrates energetic, nutrient, hormonal, redox, and stress signals to coordinate cellular and whole-body energy homeostasis. Although AMPK was initially characterized primarily as a sensor of changes in cellular AMP/ATP ratios, recent studies have revealed additional layers of regulation involving upstream kinases, post-translational modifications, heterotrimeric isoform composition, subcellular compartmentalization, and tissue-specific signaling. In this review, we provide an updated overview of the molecular mechanisms regulating AMPK activity, its major downstream metabolic and homeostatic pathways, its roles in metabolic, cardiovascular, neurodegenerative, muscular, malignant, and age-associated diseases, and current strategies for pharmacological AMPK modulation. We compare indirect activators, including metformin and naturally derived compounds, with direct small-molecule agonists targeting the allosteric drug and metabolite (ADaM) site, and emerging activators that selectively engage specific AMPK isoforms, tissues, or subcellular pools. We also discuss endogenous AMPK regulators, including microbiota-derived metabolites, and critically evaluate the potential adverse consequences of sustained or systemic AMPK activation. Collectively, current evidence indicates that the therapeutic effects of AMPK activation are highly dependent on tissue, heterotrimer composition, subcellular localization, disease stage, and the magnitude and duration of activation. Rather than indiscriminate systemic activation, future AMPK-directed therapies are therefore likely to benefit from isoform-, tissue-, and compartment-selective approaches that preferentially engage disease-relevant AMPK signaling while minimizing off-target effects. Continued characterization of AMPK signaling specificity and the development of selective pharmacological modulators should facilitate the translation of AMPK biology into more precise therapies for metabolic and other chronic diseases. Full article

(This article belongs to the Special Issue AMPK: From Mechanisms to New Therapies)

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35 pages, 5572 KB

Open AccessReview

Emerging Roles of Extracellular Vesicle-Mediated Transfer of Mitochondrial and Mitochondrial Components in Cancer

by Yue Gu, Chen Gu, Runfang Pan and Baonian Liu

Cells 2026, 15(16), 1502; https://doi.org/10.3390/cells15161502 - 20 Aug 2026

Viewed by 492

Abstract

Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate [...] Read more.

Extracellular vesicles (EVs) are crucial mediators of intercellular communication in the tumor microenvironment (TME) which facilitate the transfer of bioactive molecules including functional mitochondria and their integral components. This review summarizes the emerging role of EV-mediated mitochondrial transfer in cancer progression. We delineate the mechanisms governing the packaging of mitochondria and their constituents into EVs and subsequently highlight their multifaceted functions across various malignancies, including breast cancer, prostate cancer, blood malignancies, head and neck squamous cell carcinoma, digestive system cancers, etc. Mitochondrial cargo, such as intact mitochondria, mitochondrial DNA (mtDNA), and RNA (mtRNA), are shown to reconfigure metabolism, enhance bioenergetics, promote proliferation and invasion, induce drug resistance, and remodel TME by suppressing antitumor immunity. While previous reviews have predominantly focused on the role of mitochondrial transfer in individual cancers or specific systemic diseases, we made a comprehensive overview encompassing diverse cancer types. These findings suggest that EV-mediated mitochondrial cargo transfer represents a biological intercellular communication mechanism with implications for tumor progression and therapeutic resistance. It is worth noting that we also apply standardized evidence-grading frameworks (C1–C4) across cancer types to provide a critical assessment of the current evidence and identify key methodological gaps that must be addressed in future studies. Collectively, this review underscores the significance of EV-mediated mitochondrial transfer as an important biological process in cancer, presenting it as a promising frontier for novel diagnostic and therapeutic interventions. Full article

(This article belongs to the Special Issue Extracellular Vesicles and Exosomes: Novel Insight and Therapeutic Applications in Cancer)

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19 pages, 25622 KB

Open AccessArticle

PHGDH Promotes Synovial Aggression and Inflammation via Upregulating ADRA2A Expression in Rheumatoid Arthritis

by Kai Sun, Ting Liu, Xuanxian Xu, Huan Dong, Huijuan Hu, Chenxi Peng, Xiaofan Ge, Liuqin Liang, Youjun Xiao, Hanshi Xu and Qian Qiu

Cells 2026, 15(16), 1501; https://doi.org/10.3390/cells15161501 - 20 Aug 2026

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Abstract

Objectives: The role of Phosphoglycerate Dehydrogenase (PHGDH), the first key enzyme in the serine biosynthesis pathway, is important in controlling cancer survival; however, its role in rheumatoid arthritis (RA) remains unknown. Here, we investigated the functional involvement of PHGDH in RA pathogenesis, as [...] Read more.

Objectives: The role of Phosphoglycerate Dehydrogenase (PHGDH), the first key enzyme in the serine biosynthesis pathway, is important in controlling cancer survival; however, its role in rheumatoid arthritis (RA) remains unknown. Here, we investigated the functional involvement of PHGDH in RA pathogenesis, as well as its underlying molecular mechanisms. Methods: mRNA and protein expression in RA fibroblast-like synoviocytes (FLS) was measured by RT-qPCR and Western blot, respectively. Immunohistochemistry (IHC) was used to detect the protein expression in RA synovium. Cellular and tissue localization of the protein was assessed using IHC and immunofluorescence. The functional role of PHGDH in RA FLS was evaluated using multiple approaches: Transwell assays to assess cell migration and invasion, Annexin V/PI staining to detect apoptosis, and EdU assays to measure cell proliferation. Key downstream targets of PHGDH were identified via RNA sequencing (RNA-seq). The therapeutic potential of PHGDH targeting was further assessed in a rat collagen-induced arthritis (CIA) model following intra-articular administration of PHGDH-shRNA. Results: PHGDH expression was markedly elevated in RA synovial tissues and FLS. Functionally, knockdown of PHGDH suppressed proliferation, migration, invasion, and inflammatory cytokine production of RA FLS. Mechanistic studies revealed that PHGDH exerts its effects, at least in part, by inhibiting the expression of adrenoceptor alpha 2A (ADRA2A). The therapeutic relevance of these findings was further supported by in vivo experiments, where intra-articular delivery of PHGDH-shRNA significantly ameliorated the severity of arthritis in rats with CIA. Conclusions: Our results indicate that the PHGDH-ADRA2A axis critically drives the inflammatory and aggressive phenotype of RA FLS, suggesting that PHGDH might be as a promising therapeutic target for RA. Full article

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2 pages, 144 KB

Open AccessCorrection

Correction: Zeng et al. Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling. Cells 2022, 11, 1774

by Ling-Hui Zeng, Muhammad Qasim Barkat, Shahzada Khurram Syed, Shahid Shah, Ghulam Abbas, Chengyun Xu, Amina Mahdy, Nadia Hussain, Liaqat Hussain, Abdul Majeed, Kashif-ur-Rehman Khan, Ximei Wu and Musaddique Hussain

Cells 2026, 15(16), 1500; https://doi.org/10.3390/cells15161500 - 20 Aug 2026

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Abstract

In the original publication [...] Full article

21 pages, 2805 KB

Open AccessArticle

MitoQ Has Diverse Effects on H₂O₂-Induced Oxidative Stress and the NRF2 Signalling Pathway in Aortic Smooth Muscle Cells of Different Origins

by Simon Cornelius Haas, Bingchen Hou, Andreas Sebastian Peters, Johannes Hatzl, Dittmar Böckler and Susanne Dihlmann

Cells 2026, 15(16), 1499; https://doi.org/10.3390/cells15161499 - 20 Aug 2026

Viewed by 411

Abstract

Oxidative stress plays a central role in the development and progression of abdominal aortic aneurysms (AAA), as it severely impairs the function and survival of vascular smooth muscle cells (VSMCs). MitoQ (mitoquinone mesylate), a mitochondria-specific antioxidant, was shown to reverse age-related arterial stiffening [...] Read more.

Oxidative stress plays a central role in the development and progression of abdominal aortic aneurysms (AAA), as it severely impairs the function and survival of vascular smooth muscle cells (VSMCs). MitoQ (mitoquinone mesylate), a mitochondria-specific antioxidant, was shown to reverse age-related arterial stiffening and improve vascular endothelial function, among other things, by interacting with the NRF2 signalling pathway. The aim of this study was to compare how long-term treatment with low doses of MitoQ affects the NRF2 stress response in VSMCs, derived from different origins (AAA-SMC, healthy aortic SMC, and immortalized VSMC (iHAoSMC)). We found a significant reduction in NRF2 and KEAP1 levels in the aortic wall of patients with AAA, accompanied by increased 8-OHdG levels, indicating defects in the response to oxidative stress. In contrast, relative NRF2 expression in tissue extracts and VSMC-enriched areas was higher in patients with AAA than in healthy aortic tissue. In vitro, baseline NRF2 protein levels were significantly higher in AAA-SMC and in iHAoSMC than in VSMC from healthy aorta, whereas NRF2 activity did not differ between AAA-derived and healthy VSMC. AAA-derived SMC were found to be less vulnerable against toxic concentrations of MitoQ than healthy VSMC, and the cell viability was differentially affected by H₂O₂. Acute oxidative stress by H₂O₂ increased NRF2 activity in AAA-SMC and iHAoSMC, but not in healthy VSMC. Pre-treatment of the cells for 7 days with low-dose (10 nM) MitoQ resulted in significantly increased NRF2 activity in AAA-SMC and iHAoSMC, but not in healthy VSMC, which was accompanied by a significant reduction of ROS production, particularly in AAA-derived SMC. Our data demonstrate that prolonged treatment with low doses of MitoQ has a protective effect, particularly on VSMCs from AAA, without affecting healthy aortic VSMCs. Moreover, immortalized cells can be used as a model for investigating oxidative stress responses in AAA-SMC, even though they do not react in exactly the same way. Overall, our findings confirm the cytoprotective potential of MitoQ to limit oxidative stress, particularly in AAA-SMC that is clinically observed in the abdominal aneurysm wall. Full article

(This article belongs to the Special Issue The Role of Oxidative Stress in Cardiovascular Diseases—2nd Edition)

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17 pages, 9084 KB

Open AccessArticle

Evaluation of Curcumin as a Supplement to Improve Mitotane Effects on Adrenocortical Carcinoma

by Marta Claudia Nocito, Alice Amico, Tarig Hamad, Alessandro Cormace, Constanze Hantel, Catia Morelli, Diego Sisci, Marilena Lanzino, Vincenzo Pezzi, Ivan Casaburi and Rosa Sirianni

Cells 2026, 15(16), 1498; https://doi.org/10.3390/cells15161498 - 20 Aug 2026

Viewed by 445

Abstract

For many types of cancer, pre-clinical studies have shown that dietary interventions and supplements can be effective in reducing the toxicity and increasing the efficacy of chemotherapeutics. In this context, the polyphenol curcumin is an attractive molecule. We have previously demonstrated that curcumin [...] Read more.

For many types of cancer, pre-clinical studies have shown that dietary interventions and supplements can be effective in reducing the toxicity and increasing the efficacy of chemotherapeutics. In this context, the polyphenol curcumin is an attractive molecule. We have previously demonstrated that curcumin inhibits adrenocortical carcinoma (ACC) cell growth, has an impact on ACC cell metabolism, decreasing cholesterol availability and promoting glucose and glutamine metabolism. In this study, we evidenced that curcumin downregulates the transcription factors SF-1 and SREBPs and their targets, while inducing a ROS-dependent, HIF1α- and NRF2-mediated metabolic rewiring. NRF2 sustained an adaptive antioxidant mechanism dependent on glutamine, cysteine, and glycine uptake to support glutathione synthesis and avoid lipid peroxidation. Furthermore, the combination of curcumin with mitotane demonstrated synergistic effects in inhibiting ACC cell viability and reducing steroidogenic gene expression. These synergistic effects were observed with sub-therapeutic doses of mitotane, which are reached by patients who fail to attain the therapeutic plasma concentrations of the drug. Crucially, in vivo, curcumin administration to tumor-free mice significantly upregulated NRF2 expression and preserved liver tissue integrity. These results warrant further preclinical evaluation of the proposed combination therapy, particularly for those patients who fail to achieve or maintain mitotane plasma concentrations in the therapeutic range. Full article

(This article belongs to the Collection Research Advances in Cellular Metabolism)

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21 pages, 34456 KB

Open AccessArticle

ST6GAL1 Is a Functional Regulator of UVA-Induced Photoaging in Human Dermal Fibroblasts

by Jiangming Zhong, Ling Liang, Man Wu, Yuting Liang, Menggeng Li, Cheuk-Lun Lee and Peng Shu

Cells 2026, 15(16), 1497; https://doi.org/10.3390/cells15161497 - 20 Aug 2026

Viewed by 369

Abstract

Skin photoaging, primarily driven by UVA radiation, is characterized by the accumulation of senescent fibroblasts and the degradation of the extracellular matrix (ECM). While the roles of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) are well-documented, the regulatory impact of post-translational glycosylation [...] Read more.

Skin photoaging, primarily driven by UVA radiation, is characterized by the accumulation of senescent fibroblasts and the degradation of the extracellular matrix (ECM). While the roles of reactive oxygen species (ROS) and matrix metalloproteinases (MMPs) are well-documented, the regulatory impact of post-translational glycosylation in this process remains poorly understood. We established a UVA-induced photoaging model in human dermal fibroblasts (HDFs) and employed bulk mRNA-seq and high-throughput lectin microarrays to profile glycomic alterations. The functional role of the sialyltransferase ST6GAL1 was investigated through pharmacological inhibition of cellular sialylation (3Fax-Neu5Ac), siRNA-mediated knockdown, and gain-of-function overexpression. Mechanistic insights were gained via RAS-ERK pathway analysis and validated in a 3D reconstructed human full-thickness skin model (T-Skin™). Glycomic profiling revealed that UVA irradiation triggers a broad increase in α2,6-sialylation in HDFs. We identified ST6GAL1 as the primary enzymatic driver of this remodeling, with its expression upregulated in both photoaged HDFs and 3D skin models. Functional assays demonstrated that ST6GAL1 overexpression induces hallmark features of photoaging, including p16, MMP and γ-H2AX upregulation, G0/G1 cell cycle arrest and increased SA-β-gal activity. Conversely, pharmacological or genetic inhibition of ST6GAL1 effectively mitigated the photoaged phenotype. Mechanistically, ST6GAL1 regulates the expression of p16 via the activation of the RAS-ERK signaling cascade. Our study identifies ST6GAL1-mediated α2,6-sialylation as a novel functional hallmark of skin photoaging, highlighting the association of ST6GAL1 with the RAS-ERK-p16 axis as a potential regulator for targeting UVA-induced skin photoaging and dermal senescence. Full article

(This article belongs to the Special Issue Glycosylation and Glycoproteins in Human Disease)

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17 pages, 2654 KB

Open AccessReview

NaF-PET Imaging for Detection of Early Arterial Microcalcification and Monitoring of Targeted Therapy: A Narrative Review

by Reza Piri, Sepita Taghizadeh and Poul Flemming Høilund-Carlsen

Cells 2026, 15(16), 1496; https://doi.org/10.3390/cells15161496 - 20 Aug 2026

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Abstract

Ischemic heart disease is currently diagnosed mainly through cardiac computed tomography (CT) angiography and functional testing, both of which detect only advanced arterial macrocalcification, at a stage when treatment can merely slow disease progression rather than reverse it. Yet, macrocalcification represents the end [...] Read more.

Ischemic heart disease is currently diagnosed mainly through cardiac computed tomography (CT) angiography and functional testing, both of which detect only advanced arterial macrocalcification, at a stage when treatment can merely slow disease progression rather than reverse it. Yet, macrocalcification represents the end product of a much earlier molecular process, which is microcalcification. This process is driven by smooth muscle cell and macrophage apoptosis, matrix vesicle release, and osteogenic phenotypic transitions within the arterial intima, occurring years to decades before mineral deposits become visible on CT. [¹⁸F]Sodium fluoride (NaF) positron emission tomography (PET) exploits fluoride binding at accessible hydroxyapatite surfaces to detect increased tracer uptake associated with active mineral deposition, including mineralization occurring at a microscopic scale below the direct spatial resolution of clinical PET. Studies demonstrate that anti-atherosclerotic interventions, including statins, and tissue-nonspecific alkaline phosphatase inhibition can suppress NaF uptake even when CT-based calcium scores remain unchanged or continue to rise, a dissociation now also observed in human trials of statins and PCSK9 inhibitors. This review traces the cellular and histological basis of arterial calcification, outlines the principles and limitations of NaF-PET imaging, and evaluates its emerging role—supported by artificial intelligence-based quantification—as a tool for monitoring targeted anti-atherosclerotic treatment. Full article

(This article belongs to the Special Issue Ischemic Heart Disease: From Cellular Level to Clinical Approaches)

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19 pages, 5338 KB

Open AccessArticle

Neonatal Treatment with Astaxanthin-Loaded Stealth Solid Lipid Nanoparticles Activates the Impaired NRF2 Pathway and Reduces Hippocampal Oxidative Stress in a Mouse Model of Trisomy 21

by Laura Angelozzi, Debora Santonocito, Francesca Flotta, Beatrice Uguagliati, Marco Emili, Noemí Rueda Revilla, Carmen Martínez-Cué, Carmelo Puglia, Fiorenza Stagni and Sandra Guidi

Cells 2026, 15(16), 1495; https://doi.org/10.3390/cells15161495 - 19 Aug 2026

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Abstract

Background: Oxidative stress is an important contributor to brain abnormalities in Down syndrome (DS), but the status of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway during early postnatal development remains poorly understood. The current study aimed to investigate whether an [...] Read more.

Background: Oxidative stress is an important contributor to brain abnormalities in Down syndrome (DS), but the status of the nuclear factor erythroid 2-related factor 2 (NRF2) antioxidant pathway during early postnatal development remains poorly understood. The current study aimed to investigate whether an impairment of the NRF2 pathway is already present in the Ts65Dn mouse model of trisomy 21 at neonatal life stages and whether early treatment with astaxanthin-loaded stealth solid lipid nanoparticles (AST-SSLNs) positively impacts NRF2 signaling and reduces oxidative stress. Methods: Hippocampal NRF2 pathway components and oxidative stress markers were analyzed in neonate Ts65Dn and euploid mice. From postnatal day (P)3 to P15, mice received daily subcutaneous injections of AST-SSLNs or unloaded nanoparticles. NRF2 pathway activation, reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and safety parameters were evaluated. Results: Untreated Ts65Dn mice exhibited early impairment of the NRF2 pathway, characterized by increased BACH1, reduced NRF2 activation, and decreased HO-1 expression. Neonatal AST-SSLN treatment enhanced NRF2 activation, improved HO-1 levels, and normalized ROS accumulation, lipid peroxidation, and protein carbonylation in the hippocampus, a brain region critically impaired in DS. Treatment had no adverse effects on survival, body weight, or brain weight. Conclusions: These findings demonstrate that NRF2 pathway dysfunction is an early event in trisomy 21 and identify the neonatal period as a potential therapeutic window to counteract oxidative stress. AST-SSLNs represent a promising nanomedicine-based strategy to activate the impaired NRF2 pathway and reduce early hippocampal oxidative damage in DS. Full article

(This article belongs to the Special Issue Cellular Mechanisms and Therapeutic Potentials of Neurodevelopmental Defects)

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36 pages, 4366 KB

Open AccessArticle

Trichostatin A Modulates Ethanol Consumption and Reveals Dose- and Sex-Specific Transcriptomic Signatures in the Nucleus Accumbens Shell

by Yi Zou, Sheketha R. Hauser, Teresa J. Raba, Richard L. Bell, Zhao Lai and Tiebing Liang

Cells 2026, 15(16), 1494; https://doi.org/10.3390/cells15161494 - 19 Aug 2026

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Abstract

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on [...] Read more.

Background: Histone deacetylase inhibitors (HDACis) such as Trichostatin A (TSA) have emerged as promising epigenetic modulators of addiction-related behaviors. TSA treatment has been previously shown to decrease alcohol (ethanol) consumption with dose and sex differences. However, molecular mechanisms underlying TSA’s effects on ethanol consumption remain poorly understood. Methods: We collected the nucleus accumbens shell (NAcSh) of HAD1 rats, which has been used to investigate the impact of TSA treatment on ethanol consumption. RNA-seq profiling of NAcSh followed by IPA and GSEA analysis were conducted. Results: Gene profiling identified differentially expressed genes (DEGs) with sex- and dose-specific effects, with some genes demonstrating high fold change (FC). Males showed significantly increased Oxt and decreased Ttr expression following 1 mg/kg TSA treatment. In females, Pmch expression significantly decreased following 1 mg/kg TSA treatment, whereas Tmem179 expression increased following 2 mg/kg TSA treatment. Pathways centered on Hdac and Fkbp5 in males, and Bdnf and estrogen receptor in females were significantly enriched following TSA treatment, with distinct pathways identified at the 1 mg/kg and 2 mg/kg doses. IL1β and β-estradiol are common upstream regulators among all groups. Unexpectedly, some common DEGs between male and female comparisons have opposite responses to the same dose of TSA. GSEA analysis has identified additional gene sets, hallmark genes and microRNAs, and functions including immune response, metabolism, and estrogen response significantly associated with TSA treatment. Conclusions: This study successfully identified gene expression evidence that TSA treatment is sex- and dose-specific, underscoring the importance of considering both variables in the development of HDAC-targeted therapies for alcohol use disorders. Full article

(This article belongs to the Special Issue Epigenetic Regulation in Neuronal Development, Neurodegeneration and Regeneration)

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20 pages, 5025 KB

Open AccessArticle

Human Mesenchymal Stromal Cells Attenuate Hyperoxia-Induced Cellular Impairment of Immature Oligodendrocyte and Neurons

by Meray Serdar, Karina Kempe, Josephine Herz, Francesca Ricci, Ursula Felderhoff-Müser and Ivo Bendix

Cells 2026, 15(16), 1493; https://doi.org/10.3390/cells15161493 - 19 Aug 2026

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Abstract

Preterm infants are at high risk of developing long-term brain injury such as encephalopathy of prematurity (EoP). Hyperoxia is a major contributor to EoP, affecting white and grey matter, with immature oligodendrocytes and hippocampal neurons being particularly vulnerable. While no causal therapy is [...] Read more.

Preterm infants are at high risk of developing long-term brain injury such as encephalopathy of prematurity (EoP). Hyperoxia is a major contributor to EoP, affecting white and grey matter, with immature oligodendrocytes and hippocampal neurons being particularly vulnerable. While no causal therapy is available, mesenchymal stromal cells (MSCs) show therapeutic potential and are considered a promising candidate, although their effector mechanisms remain incompletely understood. Primary oligodendrocytes were isolated from mixed glial cultures of P0–P2 rats and hippocampal neurons from E16 rat embryos. On day 3 (oligodendrocytes) and day 5 (neurons) after isolation, cells were exposed to hyperoxia for 8 h and subsequently co-cultured indirectly with naive or hypoxic-preconditioned human MSCs (hMSCs) for 48 h under standard culture conditions. Degeneration, proliferation, differentiation and mitochondrial respiration were assessed in both cell types. Both naive and hypoxic-preconditioned hMSCs attenuated hyperoxia-induced degeneration, reduced proliferation and mitochondrial respiration failure. Although oligodendrocyte differentiation, assessed by myelin basic protein (MBP) expression, was modulated neither by hyperoxia nor by hMSC treatment, the dendritic structure in hippocampal neurons was impaired by hyperoxia and improved by hMSC treatment. Notably, hypoxic-preconditioned hMSCs showed a stronger therapeutic effect than naive hMSCs on hyperoxia-damaged hippocampal neurons. These findings indicate that indirect hMSC co-culture mitigates hyperoxia-induced impairment of immature oligodendrocytes and hippocampal neurons and that hypoxic preconditioning may modulate this effect in a cell type-specific manner. Full article

(This article belongs to the Special Issue Perinatal Brain Injury—from Pathophysiology to Therapy)

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57 pages, 3719 KB

Open AccessReview

Metabolic Outputs of the Gut Microbiome: Implications for Epilepsy

by Allison Gallucci, Xi Guo, Devika Shukla and Susan L. Campbell

Cells 2026, 15(16), 1492; https://doi.org/10.3390/cells15161492 - 19 Aug 2026

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Abstract

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 [...] Read more.

Background: Microbiome-based mechanisms have emerged as a key area of investigation in epilepsy, given the growing recognition that gut microbial communities can modulate central nervous system (CNS) function through the gut–brain axis. Epilepsy is a common chronic neurological disorder affecting more than 65 million people worldwide, and despite the availability of anti-seizure medications (ASMs), approximately 30% of patients develop drug-resistant epilepsy. Current ASMs primarily suppress seizures rather than prevent disease progression, highlighting the need for alternative therapeutic strategies. In this context, increasing evidence supports a role for microbiota-dependent pathways in modulating seizure activity and treatment responsiveness. However, the mechanistic basis of these interactions remains incompletely understood. Methods: This narrative review synthesizes findings from the existing literature to examine the role of microbiota-derived metabolites, including neurotransmitters, vitamins, and the polyphenol metabolite S-equol, in gut–brain communication relevant to epilepsy. Evidence was drawn from both preclinical animal models and clinical studies to provide an integrated, mechanistic perspective on how these pathways may influence central nervous system function and seizure susceptibility. Emphasis was placed on studies describing molecular, metabolic, and signaling mechanisms linking the gut microbiome to epileptogenesis and treatment response. Results: Current evidence indicates that communication between the gut and CNS occurs through neural pathways, such as the vagus nerve, as well as through circulating microbial metabolites. These metabolites can cross the intestinal barrier and, in some cases, the blood–brain barrier (BBB), serving as key mediators of host–microbiota signaling. Emerging studies suggest that while some microbial metabolites may directly influence neuronal hyperexcitability and seizure susceptibility, others likely exert secondary or modulatory effects through broader metabolic and immune pathways. However, the precise mechanisms underlying these interactions remain incompletely understood. Conclusions: Some microbial-derived metabolites may serve as promising biomarkers and mechanistic mediators of epilepsy; however, further investigation is needed to define the molecular and cellular pathways through which these metabolites influence seizure susceptibility and epileptogenesis. Full article

(This article belongs to the Section Cellular Metabolism)

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23 pages, 7893 KB

Open AccessArticle

Derivative Texture Analysis of Tumor Histology for Evaluating Ultrasound Nanobubble-Driven Radiation Enhancement

by Yingqi Zhang, Lakshmanan Sannachi, Kai Xuan Leong, Wenyi Yang, Deepa Sharma, Ryan Yang and Gregory J. Czarnota

Cells 2026, 15(16), 1491; https://doi.org/10.3390/cells15161491 - 19 Aug 2026

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Abstract

Microbubbles (MBs) have been used as a radiosensitizer, and their combination with ultrasound (US) has emerged as a promising strategy to improve radiotherapy outcomes in tumor treatment. Nanobubbles (NBs), which are about 1000 times smaller than MB and have enhanced stability, have been [...] Read more.

Microbubbles (MBs) have been used as a radiosensitizer, and their combination with ultrasound (US) has emerged as a promising strategy to improve radiotherapy outcomes in tumor treatment. Nanobubbles (NBs), which are about 1000 times smaller than MB and have enhanced stability, have been considered to have the potential for further radiosensitization enhancement. In this study, tumor-bearing models were treated with and without nanobubble–ultrasound (NBUS) treatment before radiotherapy (XRT) to evaluate the radiosensitization. The time intervals between the NB injection and US exposure, and between US and XRT, were optimized to maximize the therapeutic efficacy. A derivative texture analysis was applied to extract microstructural features from haematoxylin and eosin (H&E)-stained images. A one-way ANOVA test combined with a k-NN classifier and Tukey’s Honestly Significant Difference (HSD) test was used to identify the best features for assessing treatment outcomes. These were applied to H&E-stained tumor sections for evaluating microstructural alterations associated with NB-driven radiosensitization. The results indicated that both the 2 Gy and 8 Gy radiation groups showed enhanced treatment outcomes when NBUS therapy was administered before radiotherapy. Notably, NBUS + 2 Gy could achieve outcomes comparable to 8 Gy only. Additionally, a derivative texture analysis was demonstrated to be a promising and powerful technique for analyzing H&E images. This study provides a quantitative framework for assessing nanobubble-enhanced radiotherapy. Full article

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23 pages, 4195 KB

Open AccessArticle

Stimulation of Adult Muscle Stem Cells with BMPs Results in Direct Activation of Notch Pathway Genes

by Birthe Katrin Alexandra Lange, Ioanna Polydorou, Viktoriia Huryn, Angelina M. Georgieva, Shanshan You, Thomas Müller, Susanne Morales-Gonzalez, Bettina Brandt, Carmen Birchmeier, Helge Amthor and Markus Schuelke

Cells 2026, 15(16), 1490; https://doi.org/10.3390/cells15161490 - 19 Aug 2026

Viewed by 774

Abstract

Muscle stem cells (MuSCs) are the cellular source for the generation and regeneration of skeletal muscle. Proper muscle growth requires precise control over the differentiation and self-renewal of MuSCs. Signaling systems, such as bone morphogenetic proteins (BMPs) and Notch, suppress the myogenic differentiation [...] Read more.

Muscle stem cells (MuSCs) are the cellular source for the generation and regeneration of skeletal muscle. Proper muscle growth requires precise control over the differentiation and self-renewal of MuSCs. Signaling systems, such as bone morphogenetic proteins (BMPs) and Notch, suppress the myogenic differentiation of MuSCs. This allows the expansion of the progenitor pool necessary for muscle growth. To better understand the molecular mechanisms and target genes of BMPs during myogenesis, we examined the response of adult mouse MuSCs to BMP6. BMP6 stimulation of freshly isolated MuSCs suppressed myogenic differentiation. Short-term stimulation (one hour) rapidly increased the expression of classical BMP target genes, such as Id1, as well as Notch pathway genes, including Hes1, Hey1, Lfng, and Snai1. We used Cleavage Under Targets and Tagmentation (CUT&Tag) to generate whole-genome binding profiles for pSMAD1/5/9 and SMAD4, which are transcriptional effectors of the BMP pathway. This method detected dynamic binding in promoters and regulatory elements of direct BMP targets, including Notch pathway genes. Our data demonstrate that BMP6 is a potent suppressor of MuSC differentiation and reveal that a subset of well-characterized anti-myogenic genes (i.e., Hes1 and Hey1) are shared targets of the BMP and Notch pathways. Full article

(This article belongs to the Special Issue Skeletal Muscle Aging and Regeneration: Mitochondrial Health, Molecular Signaling, and Therapeutic Interventions)

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18 pages, 18052 KB

Open AccessArticle

Stage-Dependent Transmural Redistribution of NET-Associated Structures and Altered DNA Architecture in Acute Appendicitis

by Jonas Pachmann, Malik Szep, Pia Meyer zu Himmern, Max Rickes, Sara Al-Madhi, Mihailo Andric, Mirhasan Rahimli, Jessica Stockheim, Katrin Hippe, Franziska S. Karras, Ulf D. Kahlert, Roland S. Croner, Martin Herrmann and Maximilian Dölling

Cells 2026, 15(16), 1489; https://doi.org/10.3390/cells15161489 - 19 Aug 2026

Viewed by 430

Abstract

Neutrophil extracellular traps (NETs) contribute to antimicrobial defense but may promote tissue damage when produced in excess or insufficiently cleared. Acute appendicitis is characterized by neutrophil-driven inflammation, but NET-associated structures and their compartment-specific dynamics have not yet been systematically evaluated. We analyzed appendiceal [...] Read more.

Neutrophil extracellular traps (NETs) contribute to antimicrobial defense but may promote tissue damage when produced in excess or insufficiently cleared. Acute appendicitis is characterized by neutrophil-driven inflammation, but NET-associated structures and their compartment-specific dynamics have not yet been systematically evaluated. We analyzed appendiceal tissue across histopathological stages of adult appendicitis patients (n = 60), including layer-specific assessment of citrullinated histone H3 (CitH3), myeloperoxidase (MPO), B-DNA and modified DNA. In addition, we quantified NET-associated markers in the circulation of patients with histopathologically staged appendicitis (up to n = 52) and controls without appendicitis (n = 29). CitH3- and MPO-positive deposits increased with histopathological severity, formed large patches, and showed increasing involvement of the submucosa and muscularis in advanced stages. In parallel, the DNA ratio shifted toward modified DNA conformations, while B-DNA decreased. Circulating CitH3, MPO-DNA complexes, and cfDNA increased with disease stage and distinguished acute appendicitis from non-appendicitis controls. These findings suggest that acute appendicitis is not only defined by neutrophil transmigration but also by spatial and structural remodeling of NET-associated extracellular chromatin. The shift in DNA conformational patterns most likely reflects altered extracellular chromatin processing and, consequently, differential persistence of extracellular DNA. Whether circulating NET-associated markers can support diagnosis and severity stratification of appendicitis requires further validation. Full article

(This article belongs to the Special Issue Ripening and Degradation Mechanisms of Neutrophil Extracellular Traps)

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1 pages, 137 KB

Open AccessCorrection

Correction: Shin et al. Exosomal Plasminogen Activator Inhibitor-1 Induces Ionizing Radiation-Adaptive Glioblastoma Cachexia. Cells 2022, 11, 3102

by Eunguk Shin, Hyunkoo Kang, Haksoo Lee, Sungmin Lee, Jaewan Jeon, Kimoon Seong, Hyesook Youn and Buhyun Youn

Cells 2026, 15(16), 1488; https://doi.org/10.3390/cells15161488 - 19 Aug 2026

Viewed by 255

Abstract

In the original publication [...] Full article

27 pages, 5397 KB

Open AccessArticle

Isoserine Improves Spatial Memory and Remodels Synaptic and Inflammatory Gene-Expression Programs in APP/PS1 Mice

by Alessandra Saitta, Rossella Basilotta, Marika Lanza, Michele Scuruchi, Giovanna Casili, Pietro Giovani, Agata Copani, Emanuela Esposito, Salvatore Oddo and Antonella Caccamo

Cells 2026, 15(16), 1487; https://doi.org/10.3390/cells15161487 - 18 Aug 2026

Viewed by 423

Abstract

Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer’s disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and [...] Read more.

Synaptic dysfunction is a major contributor to cognitive decline in Alzheimer’s disease (AD) and represents an attractive therapeutic target. Here, we investigated whether chronic isoserine treatment improves cognition and alters the expression of synaptic-related genes in APP/PS1 mice. Isoserine was well tolerated and did not adversely affect body weight. In the Morris water maze, isoserine improved probe-trial performance in APP/PS1 mice, significantly reducing latency to the first platform-location crossing, while time spent in the target quadrant showed a directionally consistent but non-significant increase. To identify molecular correlates, we profiled 84 synaptic-related genes using a targeted RT² Profiler PCR Array. Gene-level factorial analyses identified several nominal treatment-associated effects, but no individual isoserine effect in APP/PS1 mice remained significant after false-discovery-rate correction. In contrast, module-level analyses identified False-discovery rate (FDR)-significant changes in NF-κB/inflammatory, synaptic-maintenance, and glutamatergic-signaling gene-expression modules, with significant genotype × treatment interactions for the NF-κB/inflammatory and synaptic-maintenance modules. Exploratory heatmap and principal component analyses further illustrated disease-context-dependent expression patterns. Western blot analyses showed that isoserine reduced nuclear factor kappa B (NF-κB p65) and NMDA receptor subunit GluN2B (GluN2B) and increased postsynaptic density protein 95 (PSD-95) levels in APP/PS1 mice. These findings suggest that isoserine improves spatial memory retention and coordinately remodels synaptic and inflammatory molecular programs in APP/PS1 mice. Full article

(This article belongs to the Section Cellular Neuroscience)

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42 pages, 2712 KB

Open AccessReview

Cellular and Microcircuit Mechanisms of Anesthetic Disruption of Conscious-State Organization

by Bernard Kordas

Cells 2026, 15(16), 1486; https://doi.org/10.3390/cells15161486 - 18 Aug 2026

Viewed by 391

Abstract

The reversible effects of general anesthesia can be used to examine how brain activity changes during transitions into and out of altered conscious states. Such changes are commonly tracked using behavioral responses, electroencephalographic recordings, and measures of functional connectivity. These measures, however, reflect [...] Read more.

The reversible effects of general anesthesia can be used to examine how brain activity changes during transitions into and out of altered conscious states. Such changes are commonly tracked using behavioral responses, electroencephalographic recordings, and measures of functional connectivity. These measures, however, reflect processes occurring at lower levels of organization, including the activity of pyramidal neurons, dendritic integration, interneuron function, thalamocortical signaling, and glial regulation of the extracellular environment. Anesthesia does not affect all neural processes equally. Propofol and volatile agents interfere with synaptic transmission and apical dendritic integration, as well as cortical feedback and thalamocortical signaling. The resulting activity is not necessarily absent or uniformly weaker. It is often more stereotyped, temporally restricted, and poorly coordinated between regions. Ketamine produces a different organization. Substantial neural activity and complex cortical responses may persist after behavioral responsiveness has been lost, although deeper anesthesia also produces slower and less complex activity. Responsiveness, environmental connectedness, memory, reportability, and conscious content may therefore become partly uncoupled. Ketamine produces a dissociative state that cannot be interpreted simply as another form of the predominantly restrictive state produced by propofol or volatile anesthetics. This narrative review synthesizes evidence identified through a structured PubMed search to examine how anesthesia reshapes conscious processing and why unresponsiveness or absent recall may not indicate absent experience. Full article

(This article belongs to the Special Issue Brain Function and Structure: Mapping Complexity in Neuronal Cells)

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29 pages, 10405 KB

Open AccessReview

Urine and Blood-Derived MicroRNAs in Patients with Kidney Cancer: A Review of Clinical Utility and Recent Developments

by Samuel Y. R. Chen, Serina Quach, Vladislav Nikitin, Jennifer A. Linehan and Matias A. Bustos

Cells 2026, 15(16), 1485; https://doi.org/10.3390/cells15161485 - 18 Aug 2026

Viewed by 495

Abstract

Renal cell carcinoma (RCC) is frequently detected incidentally, and no widely adopted noninvasive biomarkers are available for RCC diagnosis or prognosis. In this regard, cell-free microRNAs (cfmiRs) have emerged as promising candidates due to their stability in biological fluids. In this narrative review, [...] Read more.

Renal cell carcinoma (RCC) is frequently detected incidentally, and no widely adopted noninvasive biomarkers are available for RCC diagnosis or prognosis. In this regard, cell-free microRNAs (cfmiRs) have emerged as promising candidates due to their stability in biological fluids. In this narrative review, we summarize translational studies published from 2010 to 2025 that evaluated serum, plasma, or urinary cfmiRs for RCC diagnosis, prognosis, recurrence surveillance, or treatment-response monitoring. Forty-two studies met inclusion criteria, comprising 3454 patients with RCC and 2445 healthy donors. Twenty-nine studies assessed diagnostic performance, fewer evaluated prognostic applications, and none examined treatment-response monitoring. Multi-miRNA panels generally reported higher performance than single-miRNA assays. Serum was the most frequently studied biofluid in this review (n = 26), followed by urine (n = 12) and plasma (n = 4). Urinary biomarkers demonstrated high specificity and the practical advantage of noninvasive collection. Although limited in number, prognostic studies identified associations between cfmiRs and overall survival, recurrence-free survival, metastasis-free survival, and other clinically relevant outcomes. However, substantial heterogeneity in study design, assay methods, and reporting limited comparisons across studies. Current evidence supports continued evaluation of cfmiRs as adjunctive biomarkers alongside imaging or histopathology, but multicenter validation, standardized methods, and more robust evidence are required before clinical implementation. Full article

(This article belongs to the Special Issue MicroRNAs: Regulators of Cellular Fate)

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15 pages, 2550 KB

Open AccessArticle

Dihydroquinine Enhances Radiosensitivity in Cervical Cancer Cells Accompanied by Radiation-Induced Cellular Responses

by Ausanai Prapan, Pimvaree Aissara, Peerawit Soonthornchookiat, Chanyatip Suwannasing, Jirapas Jongjitwimol, Chatrawut Pattaweerakul, Yu Xiong, Saranya Chaiwaree and Hans Bäumler

Cells 2026, 15(16), 1484; https://doi.org/10.3390/cells15161484 - 18 Aug 2026

Viewed by 487

Abstract

Radiosensitizers are being investigated to improve the therapeutic efficacy of radiotherapy by enhancing tumor cell sensitivity while minimizing damage to normal tissues. Dihydroquinine (DHQ), a naturally occurring Cinchona alkaloid with diverse biological activities, has not previously been evaluated for radiosensitizing potential. In this [...] Read more.

Radiosensitizers are being investigated to improve the therapeutic efficacy of radiotherapy by enhancing tumor cell sensitivity while minimizing damage to normal tissues. Dihydroquinine (DHQ), a naturally occurring Cinchona alkaloid with diverse biological activities, has not previously been evaluated for radiosensitizing potential. In this study, human cervical cancer (HeLa) cells were pretreated with an IC20 concentration of DHQ and exposed to 6 MV X-ray irradiation. Clonogenic survival was assessed after irradiation at 2, 4, and 6 Gy, while intracellular ROS, γ-H2AX immunofluorescence, and apoptosis were evaluated following DHQ pretreatment and 2 Gy irradiation. DHQ pretreatment reduced clonogenic survival, yielding sensitizer enhancement ratio values of 1.37 and 1.55 at surviving fractions of 0.20 and 0.37, respectively, indicating modest-to-moderate enhancement of radiosensitivity. DHQ was also associated with increased ROS production, elevated γ-H2AX positivity, and enhanced apoptosis compared with irradiation alone. These findings suggest that DHQ enhances the radiation response in HeLa cells and is associated with increased radiation-induced cellular responses. Although the radiosensitizing effect was modest, the consistent findings across multiple biological endpoints support further investigation of DHQ as a potential adjunct to radiotherapy. Further studies are warranted to validate these findings in more clinically relevant preclinical models. Full article

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26 pages, 2010 KB

Open AccessReview

From Degeneration to Regeneration: The Evolving Landscape of Cell-Based Tendon Repair

by Ines Wang, Brett D. Owens and Jay Trivedi

Cells 2026, 15(16), 1483; https://doi.org/10.3390/cells15161483 - 18 Aug 2026

Viewed by 573

Abstract

Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and [...] Read more.

Tendinopathies represent a major clinical challenge. Vasculature, neuromuscular junctions, low cellularity, and slow extracellular matrix (ECM) turnover restrict endogenous repair and predispose injured tendons to fibrosis, mechanical weakness, and reinjury. Current therapeutic strategies including rehabilitation protocols, anti-inflammatory medications, platelet-rich plasma (PRP) injections, and surgical repair primarily address symptoms or structural deficits without correcting the underlying biological limitations of tendon healing. Cell-based therapies have emerged as a promising regenerative approach aimed at restoring tissue homeostasis through modulation of angiogenesis, collagen synthesis, immune responses, and tenogenic differentiation. Mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), tendon-derived stem cells (TDSCs), induced pluripotent stem cells (iPSCs), differentiated tenocytes, and extracellular vesicle (EV)-based products have demonstrated the ability to enhance vascularization, promote type I collagen remodeling, suppress excessive inflammation, and stimulate tenocyte lineage commitment. These effects are mediated through paracrine signaling, growth factor secretion, and activation of key pathways, including HIF-1α, TGF-β/SMAD, NF-κB, and PI3K/Akt signaling. Despite promising preclinical data, significant translational challenges remain, including limited cell survival at the injury site, variability in cell sources and dosing, immunogenicity, risk of misdifferentiation, and lack of standardization across clinical protocols. Emerging strategies such as genetic modification, hypoxic preconditioning, scaffold-based delivery systems, and extracellular vesicle engineering aim to enhance therapeutic efficacy and reproducibility. This review synthesizes current evidence on cell-based tendon repair, critically evaluates mechanistic insights, clinical trials, and translational barriers, and outlines future directions toward biologically informed regenerative therapies. Full article

(This article belongs to the Special Issue Gene and Cell Therapy in Regenerative Medicine—Third Edition)

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22 pages, 14172 KB

Open AccessArticle

Inflammation-Associated Changes in Piezo1 Expression, Mitophagy-Related Markers, and Matrix Dysregulation in an LPS-Stimulated Co-Culture Organoid System

by Kavitha Raja, Dineshwary Grace Suresh, Jamila Khalid Albeshri, Surendra Singh Rawat, Ivan James Prithishkumar, Thomas Nau and Nerissa Naidoo

Cells 2026, 15(16), 1482; https://doi.org/10.3390/cells15161482 - 18 Aug 2026

Viewed by 574

Abstract

Osteoarthritis (OA) is a progressive joint disease characterized by cartilage degeneration, chronic low-grade inflammation, and disruption of tissue homeostasis. Although the mechanosensitive ion channel Piezo1 has been implicated in OA pathogenesis, its expression may also be modulated by inflammatory stimuli independently of applied [...] Read more.

Osteoarthritis (OA) is a progressive joint disease characterized by cartilage degeneration, chronic low-grade inflammation, and disruption of tissue homeostasis. Although the mechanosensitive ion channel Piezo1 has been implicated in OA pathogenesis, its expression may also be modulated by inflammatory stimuli independently of applied mechanical loading. This study established a scaffold-free three-dimensional co-culture organoid model comprising human bone marrow-derived mesenchymal stem cell-derived chondrocyte-like cells and M-CSF/RANKL-differentiated RAW264.7-derived osteoclast-like cells to investigate Piezo1-associated molecular responses, inflammatory signaling, and mitophagy-related markers under lipopolysaccharide (LPS)-induced inflammatory conditions. Osteoclast-like differentiation was validated in parallel monolayer cultures by tartrate-resistant acid phosphatase staining and the presence of multinucleated cells before the corresponding differentiated cultures were used for organoid generation. Histological staining, immunofluorescence, CellTiter-Glo 3D viability assay, lactate dehydrogenase cytotoxicity assay, RT-qPCR, and Western blotting were used to evaluate extracellular matrix formation and inflammatory, catabolic, and mitochondrial quality-control-associated markers. LPS stimulation increased the expression of Piezo1, HIF-1α, phosphorylated CaMKII, NLRP3, cleaved Caspase-1, and MMP13, together with alterations in mitophagy- and autophagy-associated markers. Among the evaluated compounds, curcumin produced the greatest improvement in viability relative to the LPS-treated group and was selected for subsequent molecular analyses. Curcumin treatment was associated with reduced inflammatory and catabolic marker expression and partial preservation of cartilage-associated matrix markers. These findings demonstrate inflammation-associated changes in Piezo1 expression and related molecular markers but do not establish mechanically activated Piezo1 signaling or Piezo1-dependent causality. The organoid system therefore represents an exploratory LPS-induced inflammatory model exhibiting selected OA-relevant molecular and matrix-associated features. Full article

(This article belongs to the Section Stem Cells)

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23 pages, 6378 KB

Open AccessArticle

Sepsis-Induced Exosomal Transfer of MAFB mRNA Reprograms Hepatocytes via a miR-155–Jarid2–H3F3A Epigenetic Cascade

by Gizaw Mamo Gebeyehu, Milorad Zjalic, Rita Bognár, Benjámin Farkas, Shima Rashidiani, Géza Makkai, Tibor Z. Jánosi, Péter Urbán, József Kun, Attila Gyenesei, Marianna Pap, Željko Debeljak, Marija Heffer and Tibor A. Rauch

Cells 2026, 15(16), 1481; https://doi.org/10.3390/cells15161481 - 18 Aug 2026

Viewed by 649

Abstract

Exosomes carry bioactive macromolecules driving sepsis pathogenesis, but the mechanisms underlying macrophage-to-hepatocyte communication during systemic inflammation remain poorly understood. We investigated how sepsis-induced macrophage exosomes are involved in remote intercellular crosstalk with hepatic cells via transcription factor-encoding mRNA cargo. Human monocytic THP-1 macrophages [...] Read more.

Exosomes carry bioactive macromolecules driving sepsis pathogenesis, but the mechanisms underlying macrophage-to-hepatocyte communication during systemic inflammation remain poorly understood. We investigated how sepsis-induced macrophage exosomes are involved in remote intercellular crosstalk with hepatic cells via transcription factor-encoding mRNA cargo. Human monocytic THP-1 macrophages were stimulated with lipopolysaccharide (LPS), followed by exosome isolation, recipient cell uptake verification, and high-throughput RNA sequencing cargo analysis. To functionally reconstruct downstream signaling in recipient cells, exosome-enriched MAFB mRNA was transiently overexpressed in a HepG2 cell model, with subsequent expression changes mapped at both the transcript and protein levels using quantitative PCR and Western blot analyses. This ectopic MAFB expression directly upregulates the expression of microRNA-155 (miR-155). Crucially, elevated miR-155 acts as a post-transcriptional repressor that directly targets and downregulates JARID2 and H3F3A mRNAs and their corresponding protein products within the liver cells, orchestrating a “repressor-of-repressors” disinhibition cascade that drives net chromatin remodeling and activation of downstream hepatic target genes. This study demonstrates that sepsis alters exosomal transcription factor mRNA cargo and delineates a mechanistic downstream pathway—MAFB → ↑miR155 → ↓Jarid2 & ↓H3F3A → Chromatin Remodeling → Downstream Hepatic Gene Activation pathway—that provides novel, specific molecular checkpoints for therapeutic intervention in sepsis-induced liver injury. Full article

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18 pages, 2865 KB

Open AccessArticle

Functional and Structural Determinants of Human Sperm Cryoresistance: Insights from Motility, Mitochondrial and Chromatin Integrity Analyses

by Eva Tvrdá, Temidayo S. Omolaoye, Michal Ďuračka, Fawzia AlObeidli and Stefan S. Du Plessis

Cells 2026, 15(16), 1480; https://doi.org/10.3390/cells15161480 - 18 Aug 2026

Viewed by 348

Abstract

Sperm cryopreservation is essential for fertility preservation and assisted reproduction; however, post-thaw sperm quality varies markedly between individuals despite standardized protocols. This exploratory study investigated whether good and poor freezers differ in cellular, sub-cellular, and molecular features associated with cryoresistance. One ejaculate from [...] Read more.

Sperm cryopreservation is essential for fertility preservation and assisted reproduction; however, post-thaw sperm quality varies markedly between individuals despite standardized protocols. This exploratory study investigated whether good and poor freezers differ in cellular, sub-cellular, and molecular features associated with cryoresistance. One ejaculate from each of 100 normozoospermic donors was assessed before cryopreservation and after thawing. Samples were classified after thawing as good freezers (GFs; n = 50) or poor freezers (PFs; n = 50) according to post-thaw motility performance, using total motility ≥ 42% and progressive motility ≥ 30% as thresholds. Sperm quality was evaluated using computer-assisted sperm analysis, membrane and acrosome integrity assays, mitochondrial membrane potential, capacitation-associated patterns, membrane lipid disorder and DNA/chromatin integrity tests. Post-thaw thermoresistance was assessed at 37 °C for 60 and 120 min. An exploratory Western blot panel was performed only on fresh pre-freeze samples from a selected subset of 4 GF and 4 PF samples. Cryopreservation reduced sperm quality in both groups; however, PF samples showed significantly greater declines in total and progressive motility, sperm viability, membrane and acrosome integrity, mitochondrial membrane potential and thermoresistance. Exploratory Western blot data showed GF-favoring patterns for proAKAP4, SPAG6, proACR and the proACR/ACR ratio, whereas PF samples showed relatively higher ACR abundance; these molecular findings require validation in larger cohorts. Our data indicate that human sperm cryoresistance is a coordinated multi-level phenomenon involving membrane, mitochondrial, acrosomal, chromatin and flagellar resilience. This study identifies candidate functional and molecular indicators associated with cryoresistance and supports future development of pre-freeze screening strategies rather than providing a validated predictive model or clinical cut-off values. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Male Fertility)

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20 pages, 1629 KB

Open AccessReview

Transcription Factor Regulation of Epidermal Differentiation and Inflammation

by Uyanga Batzorig, Grace Zhang and George L. Sen

Cells 2026, 15(16), 1479; https://doi.org/10.3390/cells15161479 - 18 Aug 2026

Viewed by 541

Abstract

The epidermis is far more than a mechanical shield; it is a dynamic immunological interface whose structural integrity and immune homeostasis are co-regulated by interconnected transcriptional networks. This review examines how epidermal differentiation promoting transcription factors coordinate terminal keratinocyte maturation, skin barrier formation, [...] Read more.

The epidermis is far more than a mechanical shield; it is a dynamic immunological interface whose structural integrity and immune homeostasis are co-regulated by interconnected transcriptional networks. This review examines how epidermal differentiation promoting transcription factors coordinate terminal keratinocyte maturation, skin barrier formation, immune suppression, lipid metabolism, and tissue repair. In particular, Zinc finger protein 750 (ZNF750), grainyhead-like transcription factor 3 (GRHL3), and ovo-like transcriptional repressor 1 (OVOL1) integrate epidermal differentiation with the suppression of inflammatory signaling by regulating lipid metabolism, innate immune sensors, stress-response pathways, and environmentally responsive transcriptional programs. Disruption of these regulatory nodes impairs barrier integrity, amplifies inflammatory signaling, and predisposes to chronic skin diseases, including psoriasis and atopic dermatitis. Full article

(This article belongs to the Special Issue Gene Regulation in Epithelial Cells)

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12 pages, 1712 KB

Open AccessArticle

Empagliflozin Improves Post-Infarct Heart Failure Through Fibroblast Growth Factor-21 and Ketone Body Oxidation Pathway

by Dao-Fu Dai, Ines Martins, Nastaran Daneshgar, Meng Gao, Benjamin Rodriguez, Mohd Mabood Khan, Antentor Hinton, Jr., Peter A. Crawford and Chad Grueter

Cells 2026, 15(16), 1478; https://doi.org/10.3390/cells15161478 - 18 Aug 2026

Viewed by 382

Abstract

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in [...] Read more.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve outcomes in heart failure, but the mechanisms remain incompletely understood. Metabolic remodeling has been proposed as a key mediator. Methods and Results: Myocardial infarction (MI) was induced in cardiomyocyte-specific BDH1 knockout (BDH1-KO) wild-type (WT) mice and in liver-specific Fibroblast Growth Factor-21 knockout (FGF21-KO) mice. Following confirmation of reduced ejection fraction (EF), mice were randomized to empagliflozin (Empa, 10 mg/kg/day) or saline. After 4 weeks, untreated WT mice demonstrated progressive systolic dysfunction (ΔEF: −11.6 ± 6.3%), whereas Empa-treated WT mice showed significant improvement (ΔEF: 9.9 ± 4.3%). This benefit was completely abolished in BDH1-KO mice (ΔEF: −10.5 ± 2.8%) or FGF21-KO mice, suggesting that FGF21 regulation and cardiomyocyte ketone oxidation are required for Empa cardioprotection. In WT and hepatocyte-specific FGF21-KO mice, 1 week of Empa treatment increased cardiac BDH1 expression in WT but not FGF21-deficient mice. In human iPSC-cardiomyocytes, FGF21 induced BDH1 expression, whereas Empa had no direct effect on BDH1. In HepG2 liver cells, Empa increased both FGF21 and BDH1 expression. Conclusions: Empa activates the liver–heart metabolic axis. Loss of cardiomyocyte BDH1 or FGF21 production by the liver abolishes Empa-mediated improvement in post-MI cardiac function, identifying FGF21/ketone metabolism as a key mechanism of SGLT2 inhibitor cardioprotection. Full article

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

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17 pages, 2004 KB

Open AccessArticle

Cellular Senescence-Associated Gene Expression in Circulating CD4⁺, CD8⁺, CD19⁺ Lymphocytes of HNSCC Patients: Associations with Clinical Parameters

by Kamila Ostrowska, Patryk Niewinski, Igor Piotrowski, Agata Kubicka, Julia Ostapowicz, Julia Kozikowska, Aleksandra Jazikowska, Karolina Czochór, Joanna Marchlewska, Danuta Procyk, Ewa Leporowska, Wiktoria M. Suchorska, Matthew J. Yousefzadeh, Michal M. Masternak and Wojciech Golusiński

Cells 2026, 15(16), 1477; https://doi.org/10.3390/cells15161477 - 18 Aug 2026

Viewed by 836

Abstract

Senescence-associated secretory phenotype (SASP) signaling, along with key markers such as P16^INK4a/CDKN2A and LMNB1, has not been systematically studied in circulating lymphocyte subsets in head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate SASP-related genes and senescence [...] Read more.

Senescence-associated secretory phenotype (SASP) signaling, along with key markers such as P16^INK4a/CDKN2A and LMNB1, has not been systematically studied in circulating lymphocyte subsets in head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate SASP-related genes and senescence markers in peripheral CD4⁺, CD8⁺, and CD19⁺ cells and assess their clinical relevance. Expression of IL-6, IL-1β, TNFα, CXCL1, P16^INK4a/CDKN2A, and LMNB1 was measured by RT-qPCR in sorted lymphocytes from 58 HNSCC patients at baseline, 31 post-treatment, and 13 controls. Statistical analyses included nonparametric tests, correlation analyses, and survival models (Kaplan–Meier, Cox regression). In the results, LMNB1 was significantly upregulated in all lymphocyte subsets of HNSCC patients. IL-6, CXCL1, and IL-1β were elevated in CD4⁺ T cells. A coordinated co-expression network involving IL-6, CXCL1, IL-1β, P16^INK4a/CDKN2A, and LMNB1 was observed. Clinically, IL-6 in CD8⁺ T cells was associated with higher nodal stage and worse survival, while CXCL1 in CD19⁺ B cells independently predicted survival. No differences were found between pre- and post-treatment samples. Circulating lymphocytes in HNSCC display coordinated expression of selected senescence-associated genes, with IL-6 and CXCL1 as candidate prognostic biomarkers linked to tumor progression that warrant further validation. Full article

(This article belongs to the Special Issue Emerging Mechanisms and Therapeutic Strategies in Head and Neck Cancer)

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22 pages, 23671 KB

Open AccessArticle

Live-Cell Imaging of Telocyte-like Cells in Primary Liver Cell Cultures

by Nikolaus Bresgen and Hubert H. Kerschbaum

Cells 2026, 15(16), 1476; https://doi.org/10.3390/cells15161476 - 18 Aug 2026

Viewed by 355

Abstract

Telocytes are small mesenchymal cells with unknown hepatic functions. In primary cultures of rat hepatocytes and non-parenchymal liver cells (NPLC), we observed, at a very low incidence, small-sized, highly motile cells. Because these cells fulfill ultrastructural/morphological ‘telocytes hallmarks’, foremost their minuteness and the [...] Read more.

Telocytes are small mesenchymal cells with unknown hepatic functions. In primary cultures of rat hepatocytes and non-parenchymal liver cells (NPLC), we observed, at a very low incidence, small-sized, highly motile cells. Because these cells fulfill ultrastructural/morphological ‘telocytes hallmarks’, foremost their minuteness and the presence of very thin telopodia, we refer to them as hepatic telocyte-like cells (hTCLs). Unique among hepatic cells and beyond these telocyte characteristics is their high motility and pronounced cell plasticity. Surprisingly, hTCLs display an exceptional exploratory behavior by moving along/between cell borders as well as beneath cells. Their fast motility apart, hTCLs share structural and behavioral similarities with Kupffer cells/macrophages in NPLC cultures, suggesting a relationship between both cell types that needs to be addressed by further investigation. In EGF/insulin-treated hepatocyte cultures, hTCLs’ motility declines, and the cells adopt an extremely small cell body with very long processes. In cultured hepatocyte monolayers, hTCLs associate with dividing hepatocytes, especially during advanced mitosis (cytokinesis). In conclusion, our observations demonstrate the presence of a small population of highly mobile, telocyte-like cells in liver-derived cell cultures, and a correlative association between hTCLs and hepatocytes, hypothetically accounting for an integrative function of this cell type. Full article

(This article belongs to the Special Issue Physiology of Telocytes)

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Cells, Volume 15, Issue 16 (August-2 2026) – 77 articles

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