Cells

41 pages, 16972 KB

Open AccessSystematic Review

Copper, Ceruloplasmin, Zinc, and Manganese Levels in Brain and Biological Fluids from Parkinson’s Disease Patients: Systematic Review and Meta-Analysis

by Félix Javier Jiménez-Jiménez, Hortensia Alonso-Navarro, Elena García-Martín, Miguel Angel Martín-Gómez, Paula Salgado-Cámara, Alba Cárcamo-Fonfría, Margarita Arroyo-Solera and José A. G. Agúndez

Cells 2026, 15(3), 288; https://doi.org/10.3390/cells15030288 - 3 Feb 2026

Abstract

The present systematic review and meta-analysis aims to establish whether the brain, cerebrospinal fluid (CSF), serum/plasma whole blood, urine, and hair levels of copper, ceruloplasmin, zinc, and manganese are related to the risk for Parkinson’s disease (PD). We reviewed the PubMed and Web [...] Read more.

The present systematic review and meta-analysis aims to establish whether the brain, cerebrospinal fluid (CSF), serum/plasma whole blood, urine, and hair levels of copper, ceruloplasmin, zinc, and manganese are related to the risk for Parkinson’s disease (PD). We reviewed the PubMed and Web of Science Core Collection databases from 1966 to 29 November 2025, and identified references of interest for this topic. We performed the meta-analysis of eligible studies that followed the PRISMA and MOOSE guidelines, with the R software package meta R 4.2.0 version. When compared to age- and sex-matched controls, PD patients showed decreased concentrations of copper in the substantia nigra and other brain areas, a trend towards increased CSF and decreased serum/plasma copper levels, decreased serum/plasma ceruloplasmin levels, decreased zinc levels in serum/plasma and increased zinc in whole blood and hair, and increased hair manganese levels. These results suggest an association between these transition metals and risk for PD. Full article

► Show Figures

Figure 1

20 pages, 9732 KB

Open AccessArticle

Identification of Natural Compounds Triggering MRGPRX2-Mediated Calcium Flux and Degranulation in RBL-2H3 Cells

by Lihui Zhang, Jing Liu, Jian Zheng, Wenguang Jing, Wenjuan Zhang, Jia Chen, Xinyue Zhang, Xianlong Cheng and Feng Wei

Cells 2026, 15(3), 287; https://doi.org/10.3390/cells15030287 - 3 Feb 2026

Abstract

Natural compounds have experienced increasing clinical application, but their association with rapid-onset anaphylactoid reactions (ARs) present a significant challenge to their safe use. These ARs, clinically resembling Type I hypersensitivity, are non-IgE-mediated and involve direct mast cell activation, primarily through the human Mas-related [...] Read more.

Natural compounds have experienced increasing clinical application, but their association with rapid-onset anaphylactoid reactions (ARs) present a significant challenge to their safe use. These ARs, clinically resembling Type I hypersensitivity, are non-IgE-mediated and involve direct mast cell activation, primarily through the human Mas-related G protein-coupled receptor X2 (MRGPRX2). We computationally screened a natural compound library for MRGPRX2 activation. A human MRGPRX2-expressing cell model was established. Cell viability assays (0–80 μM) were performed to determine appropriate drug concentrations. Compared to the controls, Baohuoside I (10 μM), along with Kaempferol-3-O-rutinoside, Epigallocatechin gallate (EGCG), Isochlorogenic Acid B, Baicalin, Andrographolide, Isorhamnetin, and Dehydroandrographolide (all at 20 μM), significantly increased intracellular calcium flux (p < 0.05) and boosted tryptase and β-hexosaminidase secretion (ELISA) (p < 0.05) in mast cells. Furthermore, the degranulation induced by these compounds was inhibited by the MRGPRX2 inhibitor Z3578 at 20 μM. Neutral red staining was employed to observe cellular morphological changes. Specific compounds capable of mediating ARs through MRGPRX2 activation on mast cells were identified. This contributes to safer and more effective drug use by elucidating the potential triggers of ARs. Full article

(This article belongs to the Special Issue Cellular and Molecular Insights into Allergies and Allergic Diseases)

► Show Figures

Figure 1

22 pages, 4698 KB

Open AccessArticle

Neuroimmune Activation in a Goat Model of Intervertebral Disc Degeneration

by Janai A. Augustin, Kevin G. Burt, Caitlin Barrett, Matthew Fainor, Brianna S. Orozco, Thomas P. Schaer, Harvey E. Smith, Robert L. Mauck and Sarah E. Gullbrand

Cells 2026, 15(3), 286; https://doi.org/10.3390/cells15030286 - 3 Feb 2026

Abstract

Intervertebral disc degeneration (IVDD) initiates a cascade of structural and biological changes that compromise mechanical function, often leading to chronic pain. While small animal models have provided insight into inflammatory and nociceptive mechanisms of IVDD, translational studies require large animal models that more [...] Read more.

Intervertebral disc degeneration (IVDD) initiates a cascade of structural and biological changes that compromise mechanical function, often leading to chronic pain. While small animal models have provided insight into inflammatory and nociceptive mechanisms of IVDD, translational studies require large animal models that more closely replicate human spine anatomy and physiology. This study induced cervical disc degeneration via intradiscal chondroitinase ABC (ChABC) injection in a large animal model and evaluated the associated disc pathology and neuroinflammatory responses across IVDs and within spinal cord and dorsal root ganglia (DRG) tissues. Results confirmed structural degeneration at ChABC-injected levels and revealed additional evidence of adjacent segment degeneration. Neuroinflammatory analyses revealed innervation, via deposition of PGP9.5 and NFH, throughout both ChABC-injected and adjacent IVDs. Monocyte markers were significantly increased in ChABC-degenerated IVDs. Across experimental groups, the level of monocyte (Ly6C) and macrophage (CD68) markers correlated with worsened histological scores and with reduced mechanical integrity. Similarly, increased production of the neuropeptide, Substance P, in IVDs was significantly positively correlated with compromised IVD mechanical function. Finally, we observed elevated production of the microglia marker, Iba1, and Substance P production in the spinal cord, with similar trends in DRGs, in degenerative spines. By establishing quantitative relationships between disc pathology, immune responses, and neural activation, this work established possible disease-contributing neuroinflammatory activation and further validated a clinically relevant model for preclinical evaluation of regenerative and therapeutic strategies. Full article

(This article belongs to the Special Issue Novel Insights into Mechanism and Treatment of Degenerative Disc Disease)

► Show Figures

Figure 1

17 pages, 1818 KB

Open AccessArticle

Targeting the c-Met/VEGFR Pathway to Boost Nab-Paclitaxel Efficacy in Gastric Cancer: Preclinical Insights

by Jennifer Huang, Quinn Kaurich, Md Sazzad Hassan, Urs von Holzen and Niranjan Awasthi

Cells 2026, 15(3), 285; https://doi.org/10.3390/cells15030285 - 3 Feb 2026

Abstract

Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and [...] Read more.

Combination chemotherapy regimens are commonly employed to treat advanced gastric adenocarcinoma (GAC), yet median survival remains less than one year. Nab-paclitaxel has demonstrated significant antitumor activity in preclinical GAC models. Overexpression of growth factors and their receptors is prevalent in GAC and contributes to its pathophysiology, with aberrant activation of the HGF/c-Met pathway reported in up to 50% of patients. We hypothesized that merestinib, a small-molecule inhibitor of c-Met, Axl, and DDR1/2, would enhance the therapeutic response to nab-paclitaxel in GAC. In high c-Met–expressing MKN-45 peritoneal dissemination xenografts in female NOD/SCID mouse models, animal survival was 17 days in controls, 37 days with nab-paclitaxel (118% increase), 24 days with merestinib (41% increase), and 43 days with the combination (153% increase), demonstrating significantly enhanced survival compared with either monotherapy. In MKN-45 subcutaneous xenografts, tumor volumes in the control, nab-paclitaxel, merestinib, and combination groups were 503 mm³, 115 mm³, 91 mm³, and −9.7 mm³ (indicating tumor regression), respectively. In low c-Met-expressing SNU-1 xenografts, tumor volumes were 219 mm³, 105 mm³, 131 mm³, and 57 mm³, respectively. IHC analysis of tumor cell proliferation and microvessel density in MKN-45 tumors supported these findings. In vitro, nab-paclitaxel and merestinib each reduced cell proliferation in GAC-associated cells, with enhanced inhibitory effects when used in combination. In MKN-45 cells, merestinib increased the expression of pro-apoptotic proteins and decreased phosphorylation of c-Met, EGFR, IGF-1R, ERK, and AKT. These results indicate that combining merestinib with nab-paclitaxel may represent a promising therapeutic strategy to improve outcomes for patients with GAC. Full article

(This article belongs to the Special Issue Gastrointestinal Cancer: From Cellular and Molecular Mechanisms to Therapeutic Opportunities)

► Show Figures

Figure 1

21 pages, 3180 KB

Open AccessArticle

Stress-Inducible Transcription Factor NUPR1 Is Involved in the Inhibitory Effects Exerted by Statins on Insulin Action in ER-Positive Breast Cancer Cells

by Domenica Scordamaglia, Azzurra Zicarelli, Francesca Cirillo, Marianna Talia, Ernestina Marianna De Francesco, Roberta Malaguarnera, Marcello Maggiolini and Rosamaria Lappano

Cells 2026, 15(3), 284; https://doi.org/10.3390/cells15030284 - 2 Feb 2026

Abstract

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC [...] Read more.

Obesity is frequently associated with metabolic alterations like hypercholesterolemia and hyperinsulinemia and represents a major risk factor for several diseases, including breast cancer (BC). Insulin signaling, as well as the frequent overexpression of the insulin receptor (IR), play a key role in BC progression. Emerging evidence suggests that the widely prescribed lipid-lowering drugs, named statins, may reduce the risk of recurrence and blunt BC cell proliferation, mainly inhibiting the HMGCR-dependent activation of the mevalonate pathway. In this study, we investigated the effects of simvastatin, atorvastatin and rosuvastatin in BC cells stimulated by insulin. To this end, we used as a BC model system MCF7 cells and naturally immortalized BCAHC-1 cells, which are characterized by high IR-expression levels. Our investigation demonstrates that statins reduce the proliferation and clonogenic capacity of BC cells prompted by insulin treatment. Mechanistically, statins impair the IR-mediated signaling and downregulate the stress-inducible transcription factor NUPR1, a known regulator of cancer progression. Importantly, NUPR1 inhibition blunted the stimulatory action of insulin on BC cells. Consistent with these findings, survival analyses of large cohorts of patients revealed that high levels of NUPR1 are associated with poor BC prognosis. Overall, our results provide novel mechanistic evidence supporting the repositioning of statins in BC, particularly in tumors characterized by elevated IR expression and activity. Full article

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

19 pages, 4511 KB

Open AccessArticle

SATB2 Induces Malignant Transformation and Cancer Stem Cell Characteristics, and Inhibition of Its Expression Reverses Drug Resistance in Mesothelioma

by Cynthia Brown, Shivam Srivastava, Rohit Srivastava, Rashmi Srivastava, Jason Morvant, Anju Shrivastava and Rakesh K. Srivastava

Cells 2026, 15(3), 283; https://doi.org/10.3390/cells15030283 - 2 Feb 2026

Abstract

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether [...] Read more.

SATB2 (special AT-rich binding protein 2) functions as a chromatin-associated epigenetic regulator that modulates gene expression, in part by serving as a transcriptional cofactor. This study assessed whether SATB2 overexpression is sufficient to promote in vitro transformation of human mesothelial cells and whether SATB2 suppression in mesothelioma cancer stem cell (CSC)–enriched populations is associated with altered chemoresistance. SATB2 expression was high in human malignant pleural mesothelioma (MPM) cell lines but absent in Met5A mesothelial cells. Ectopic SATB2 expression in Met5A cells was associated with acquisition of malignant and stem cell–like phenotypes, including increased expression of stem cell markers and pluripotency-associated factors, as well as anchorage-independent growth in soft agar and spheroid formation in suspension culture. In contrast, Met5A cells transduced with an empty vector did not form colonies or mesospheres. SATB2 overexpression in Met5A cells was also associated with increased motility, migration, and invasion, accompanied by induction of epithelial–mesenchymal transition (EMT)–related transcription factors relative to empty vector controls. Conversely, shRNA-mediated SATB2 knockdown in an MPM cell line attenuated proliferation, EMT-associated features, and CSC-like characteristics. Chromatin immunoprecipitation assays identified SATB2 occupancy at promoter regions of Bcl2, XIAP, KLF4, c-Myc, NANOG, and SOX2, consistent with a role in transcriptional regulation of genes linked to transformation, pluripotency, cell survival, proliferation, and EMT. In CSC-enriched cells, SATB2 inhibition was associated with increased sensitivity to cisplatin and pemetrexed, concomitant with reduced OCT4 and SOX2 expression. Collectively, these findings support SATB2 as a candidate therapeutic target in MPM and suggest that SATB2 suppression may enhance chemotherapy response when combined with standard agents. Full article

(This article belongs to the Special Issue The Function of Stem Cells in the Biomedical Applications)

► Show Figures

Figure 1

18 pages, 3407 KB

Open AccessArticle

SMG6’s PIN (PilT N-Terminus) Domain Is Required for Nonsense-Mediated mRNA Decay (NMD) In Vivo

by Baihui Chai, Xiao Tan, Yan Li, Chengyan Chen, Xin Ma and Tangliang Li

Cells 2026, 15(3), 282; https://doi.org/10.3390/cells15030282 - 2 Feb 2026

Abstract

Nonsense-mediated mRNA decay (NMD) is a highly conserved RNA quality and quantity surveillance machinery in eukaryotic cells, serving as an important node in the post-transcriptional gene expression. Previous studies using the complete knockout of individual NMD factors in cells or animals reveal that [...] Read more.

Nonsense-mediated mRNA decay (NMD) is a highly conserved RNA quality and quantity surveillance machinery in eukaryotic cells, serving as an important node in the post-transcriptional gene expression. Previous studies using the complete knockout of individual NMD factors in cells or animals reveal that NMD deficiency causes developmental defects and compromises tissue homeostasis. However, because most NMD factors participate in multiple molecular functions, a direct link between NMD and cell fate determination is missing. SMG6 is a core NMD effector and the only endoribonuclease among all NMD factors. The NMD function of SMG6 is exclusively mediated by its PIN (PilT N-terminus) domain. In this study, we engineered a mouse model with the capability of specifically deactivating the SMG6’s PIN domain/endoribonuclease activity (Smg6-PIN^F/F), but not knocking out the complete SMG6 protein. We found that SMG6’s PIN domain is essential for NMD activity in embryonic stem cells (ESCs) and various tissues of adult mice. Furthermore, loss of SMG6’s PIN domain is dispensable for the mouse ESC self-renewal, but severely compromises the differentiation, which consequently causes the mutant mice to die during the process of organogenesis. Through the induced deletion of SMG6’s PIN domain in adult mice, we found that loss of SMG6’s NMD function affects the homeostasis of several mouse tissues, including the testis and the intestine. In sum, our study establishes a mechanistic link between NMD per se and cell fate determination of mouse ESCs, as well as in the tissues of adult mice, where cell fate transitions are actively ongoing. The Smg6-PIN^F/F mouse line could be a valuable strain for elucidating the biology of NMD per se. Full article

(This article belongs to the Special Issue Post-Transcriptional Control of Stem Cell Fate and Neural Development)

► Show Figures

Figure 1

22 pages, 11282 KB

Open AccessArticle

Effects of N-Acetylcysteine and Alpha-Ketoglutarate on OVCAR3 Ovarian Cancer Cells: Insights from Integrative Bioinformatics and Experimental Validation

by Yasaman Khamineh, Sanaz Panahi-Alanagh, Samaneh Zolghadri, Laleh Mavaddatiyan, Ireneusz Ryszkiel, Agata Stanek and Mahmood Talkhabi

Cells 2026, 15(3), 281; https://doi.org/10.3390/cells15030281 - 2 Feb 2026

Abstract

Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; [...] Read more.

Ovarian cancer remains one of the leading causes of cancer-related mortality among women, underscoring the need for novel combination strategies that effectively inhibit tumor cell growth while limiting adverse effects. N-acetylcysteine (NAC) and alpha-ketoglutarate (AKG) are biologically active compounds with reported anticancer properties; however, their combined effects in ovarian cancer are not well characterized. In this study, we applied an integrative approach combining network pharmacology analysis with in vitro experiments to investigate the effects of NAC and AKG on OVCAR3 ovarian cancer cells. Common molecular targets of NAC and AKG were identified by intersecting predicted compound targets with ovarian cancer-associated genes, followed by protein–protein interaction network construction and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Experimental validation assessed the effects of NAC and AKG, alone and in combination, on cell viability, apoptosis, migration, and clonogenic capacity. Network analysis identified 70 shared target genes enriched in pathways related to apoptosis, cellular stress responses, and cell migration. In vitro experiments demonstrated that combined treatment with NAC (10 mM) and AKG (100 µM) significantly reduced cell viability, increased apoptotic cell death, and markedly suppressed cell migration and colony formation compared with single-agent treatments. Overall, these findings indicate that the combination of NAC and AKG exerts enhanced inhibitory effects on ovarian cancer cell growth and motility in vitro. Full article

(This article belongs to the Special Issue Genomics and Cellular Mechanisms in Ovarian Cancer)

► Show Figures

Figure 1

12 pages, 427 KB

Open AccessArticle

Interleukin-38: A Candidate Biomarker for Disease Severity in Advanced Steatotic Liver Disease

by Valeria Wagner, Michael Mederer, Barbara Enrich, Veronika Cibulkova, Johanna Piater, Andreas Zollner, Rebecca Giquel-Fernandes, Herbert Tilg and Maria Effenberger

Cells 2026, 15(3), 280; https://doi.org/10.3390/cells15030280 - 2 Feb 2026

Abstract

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD [...] Read more.

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD (n = 176) and healthy controls (n = 8). We tested group differences using Mann–Whitney U or Kruskal–Wallis; determined diagnostic quality using ROC curves. Logistic regression was used to assess the relationship with decompensation. Associations with MELD and routine laboratory parameters were modeled using Spearman correlation and linear regression. We analyzed survival using Kaplan–Meier and Cox regression. Findings: IL-38 concentrations were found to be higher in decompensated (n = 94) than in compensated patients (n = 82) (p < 0.001). MELD was positively associated with IL-38 (p < 0.001; 95% CI 0.057–0.120). This corresponds to a 9.2% increase in IL-38 per 1-point increase in MELD (95% CI 5.9–12.7%). IL-38 correlated positively with the MELD score (p < 0.001) and with bilirubin/AST/LDH. In the combination model (MELD + IL-38 ± CRP), a very good AUC ≈ 0.92 was achieved. Conclusion: IL-38 reflects the severity of steatotic liver disease and is therefore a potentially predictive biomarker for early risk stratification and therapy monitoring. Full article

► Show Figures

Figure 1

15 pages, 1969 KB

Open AccessArticle

Effect of the G-Protein-Coupled Receptor T2R14 on Proliferation and Cell Population Growth in Oral Cancer Cells

by Yongqiang Chen, Manikanta Kella, Kayla Austin, Rajinder P. Bhullar and Prashen Chelikani

Cells 2026, 15(3), 279; https://doi.org/10.3390/cells15030279 - 1 Feb 2026

Abstract

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is [...] Read more.

Oral cancer is a leading cause of cancer-related deaths and significantly affects the quality of life of patients. However, many of its mechanisms remain unclear, and its treatment needs improvement. The G-protein-coupled receptor taste receptor type 2 member 14 (T2R14 or TAS2R14) is expressed in various cancer types. However, few studies have investigated its roles in oral cancer, and its effects on oral cancer cell proliferation and growth are unknown. This study aimed to examine T2R14’s impact on proliferation and cell population growth (CPG) of oral cancer cells. TAS2R14 gene knockout was performed, and cell numbers, cell viability, and colony formation were measured. This study showed that TAS2R14 knockout in oral cancer cells significantly decreased calcium mobilization, increased cell numbers, colony formation, the proliferation marker proliferating cell nuclear antigen, and the phosphorylation of mechanistic target of rapamycin, but did not affect cell viability. These observations are consistent with the clinical data that higher TAS2R14 mRNA expression is associated with better survival of patients with oral cancer. Therefore, T2R14 downregulation increased oral cancer CPG, suggesting a tumor-suppressor-like role. The study’s findings could improve our understanding of T2R14 mechanisms and help develop strategies to advance oral cancer treatment by targeting T2R14. Full article

(This article belongs to the Special Issue G Protein-Coupled Receptors and Diseases)

► Show Figures

Graphical abstract

31 pages, 1115 KB

Open AccessReview

Peculiar Cat with Many Lives: PUMA in Viral Infections

by Zbigniew Wyżewski, Justyna Stępkowska, Pola Pruchniak, Adrianna Niedzielska, Karolina Paulina Gregorczyk-Zboroch and Matylda Barbara Mielcarska

Cells 2026, 15(3), 278; https://doi.org/10.3390/cells15030278 - 1 Feb 2026

Abstract

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; [...] Read more.

Apoptosis is a natural mechanism that shapes morphogenesis and helps maintain tissue homeostasis in healthy organisms. It is also extensively studied in the context of pathologies such as cancer and viral infections. The course of the latter strictly depends on host cell viability; therefore, regulators of apoptosis may play essential roles in distinct viral infections as well as virus-dependent diseases. The p53-upregulated modulator of apoptosis (PUMA), a pro-apoptotic member of the B-cell lymphoma 2 (Bcl-2) family, directly disrupts mitochondrial integrity, thereby promoting the intrinsic apoptotic pathway. PUMA-mediated cell death act as a double-edged sword that may either facilitate viral infection and its consequences or counteract them, depending on the infectious agent and the complex context of pathogen–host interactions. Accordingly, various viruses have evolved strategies to modulate host cell viability to their advantage by targeting PUMA—either by suppressing transcription of the PUMA gene, binding and inactivating the PUMA protein, or, conversely, inducing its production. In this work, we describe the role of PUMA in infections caused by distinct viruses and in associated diseases, viral strategies for modulating PUMA-related signaling pathways, and potential therapeutic implications. Full article

► Show Figures

Figure 1

21 pages, 3031 KB

Open AccessArticle

The Effects of BRCA1 and BRCA2 Promoter Methylation on Clinicopathological Characteristics and Clinical Outcomes in HGSOC

by Katarina Živić, Ivana Boljević, Milica Nedeljković, Milana Matović, Radmila Janković and Miljana Tanić

Cells 2026, 15(3), 277; https://doi.org/10.3390/cells15030277 - 1 Feb 2026

Abstract

Ovarian cancer is a highly lethal disease. Tumors with a deficiency in the homologous recombination repair pathway (HRD) resulting from mutations in BRCA1/2 genes have a favorable response to platinum-based chemotherapy and targeted therapy with PARP inhibitors (PARPi) mediated by synthetic [...] Read more.

Ovarian cancer is a highly lethal disease. Tumors with a deficiency in the homologous recombination repair pathway (HRD) resulting from mutations in BRCA1/2 genes have a favorable response to platinum-based chemotherapy and targeted therapy with PARP inhibitors (PARPi) mediated by synthetic lethality. Promoter methylation of BRCA1/2 genes was previously associated with HRD, but little is known about whether it translates to clinical benefit. Here, we evaluated the prevalence of BRCA1/2 promoter methylation in HGSOC patients from Serbia and examined their clinicopathological characteristics and the effect on progression-free and overall survival. Using methylation-specific PCR, we screened for hypermethylation in the promoter region of BRCA1/2 genes in a cohort of 244 patients. We found fully methylated BRCA1 and BRCA2 promoter in 4.1% and 0.45% of patients, and 23.36% and 11.21% intermediately methylated cases, respectively. Full BRCA1/2 promoter methylation was significantly associated with younger age of onset (55 and 58 years, respectively) compared to BRCA1/2-mutated cases, suggestive of BRCAness phenotype. However, in the exploratory analysis of 68 patients with clinical follow-up, we did not find a strong survival advantage for BRCA1/2 methylated over BRCA1/2-intact cases, yet more moderate effects cannot be ruled out due to the cohort size. Full article

(This article belongs to the Special Issue Cellular and Molecular Insights into Gynecologic Tumors)

► Show Figures

Figure 1

22 pages, 4059 KB

Open AccessArticle

Mitochondria and Lipid Defects in Hereditary Progranulin-Related Frontotemporal Dementia

by Jon Ondaro, Jose Luis Zúñiga-Elizari, Mónica Zufiría, Maddi Garciandia-Arcelus, Ángela Sánchez Molleda, Miren Zulaica, Miguel Lafarga, Javier Riancho, Adolfo López de Munaín, Fermin Moreno, Francisco Javier Gil-Bea and Gorka Gerenu

Cells 2026, 15(3), 276; https://doi.org/10.3390/cells15030276 - 1 Feb 2026

Abstract

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in [...] Read more.

Frontotemporal dementia (FTD) is a neurodegenerative disorder predominantly affecting individuals under 65 years of age, characterized by significant behavioral and language disabilities. Despite extensive research efforts, effective treatments for FTD remain elusive. Familial cases of FTD have been linked to genetic mutations in several key genes, among these, mutations in granulin (GRN) account for 5–20% of cases, leading to haploinsufficiency of progranulin (PGRN), a multifunctional glycoprotein. This study investigates the cellular pathology associated with GRN insufficiency by using fibroblasts derived from FTD patients carrying the c.709-1G>A GRN mutation (FTD-GRN). These fibroblasts exhibited pathological hallmarks of FTD, including lysosomes, autophagosomes, and lipofuscin accumulation, mirroring observations in affected patient tissues. Notably, we report mitochondrial abnormalities, characterized by mitochondrial swelling which is associated with decreased mitochondrial respiration, and lipid droplet accumulation, reflecting altered lipid metabolism. Experimental supplementation with recombinant human progranulin (rhPGRN) was associated with recovery of lysosomal acidification and attenuation of mitochondrial and lipid abnormalities in vitro. This study reveals that GRN haploinsufficiency induces mitochondrial and lipid dysfunctions, suggesting that these pathways may contribute to FTD-GRN pathogenesis and could be of interest for therapeutic development. Full article

(This article belongs to the Section Cellular Neuroscience)

► Show Figures

Figure 1

11 pages, 748 KB

Open AccessReview

The Emerging Roles of GlycoRNAs in the Pathogenesis of Sepsis

by Xiang Li, Saichaitanya Nallajennugari, Joshua Fu, Anfal Faisal and Mingui Fu

Cells 2026, 15(3), 275; https://doi.org/10.3390/cells15030275 - 1 Feb 2026

Abstract

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. [...] Read more.

Sepsis is a life-threatening condition caused by a dysregulated host immune response to infection, leading to systemic inflammation, organ dysfunction, and potentially death. Despite significant advances in understanding the pathophysiology of sepsis, effective therapeutic options remain limited, and mortality rates remain unacceptably high. Therefore, a deeper understanding of sepsis pathogenesis and the identification of novel therapeutic targets are urgently needed to improve patient outcomes. Recent studies have revealed that RNAs can undergo glycosylation, generating a previously unrecognized class of molecules known as glycosylated RNAs (glycoRNAs), which are localized on the outer surface of cells. GlycoRNAs are highly expressed in immune cells, and accumulating evidence indicates that they play important roles in regulating immune responses, including immune cell adhesion and infiltration, immune cell activation, and immune evasion. In addition, glycoRNAs are abundantly expressed on the epithelial cell surfaces of the respiratory, digestive, urinary, and reproductive systems, suggesting that glycoRNAs may function as a component of epithelial barriers that protect against pathogenic invasion. Collectively, these findings suggest that glycoRNAs may play a critical role in the pathogenesis of sepsis. This review summarizes the expression and functions of glycoRNAs in immune and barrier systems and highlights their potential roles during distinct immunological phases of sepsis. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Sepsis: Pathogenesis, Immune Response, and Therapeutic Strategies)

► Show Figures

Figure 1

25 pages, 3301 KB

Open AccessArticle

Three-Dimensional Human Liver Micro Organoids and Bone Co-Culture Mimics Alcohol-Induced BMP Dysregulation and Bone Remodeling Defects

by Yuxuan Xin, Guanqiao Chen, Mohammad Majd Hammour, Xiang Gao, Fabian Springer, Elke Maurer, Andreas K. Nüssler and Romina H. Aspera-Werz

Cells 2026, 15(3), 274; https://doi.org/10.3390/cells15030274 - 1 Feb 2026

Abstract

Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. [...] Read more.

Hepatic osteodystrophy (HOD) is a frequent complication of chronic liver disease, marked by impaired osteogenesis and elevated fracture risk, particularly under sustained alcohol exposure. Bone morphogenetic proteins (BMPs), which play a crucial role in maintaining bone homeostasis, are dysregulated in alcoholic liver disease. Specifically, decreased BMP2 and increased BMP13 have been linked to impaired osteogenesis and cartilage-like shifts in bone progenitors. A human in vitro system that recapitulates this hepatic BMP imbalance is needed to dissect mechanisms and identify targets. To address this, we established a long-term human three-dimensional liver–bone co-culture model that integrates hepatocytes (HepaRG), hepatic stellate cells (LX-2), and human umbilical vein endothelial cells (HUVECs) with bone scaffolds seeded with osteoblast precursors (SCP-1) and osteoclast precursors (THP-1). This study aimed to characterize the effects of chronic 50 mM alcohol exposure on hepatic fibrogenic activation and BMP ligand secretion, and to investigate the associated BMP-responsive signaling involved in bone cell lineage differentiation and functional activity. The results demonstrated alcohol-induced hepatic CYP2E1 activation and fibrogenic remodeling with EMT signatures, as well as a decrease in BMP2 and an increase in BMP13, without affecting BMP9. Liver-derived factors activated both canonical and non-canonical BMP signaling in bone progenitors, reduced osteoblast activity and mineralization, preserved osteoclast TRAP activity, and shifted the lineage toward chondrogenesis (SOX9↑, RUNX2↓). Notably, this BMP profile and skeletal phenotype reflect clinical observations in chronic liver disease, indicating that the model recapitulates key in vivo pathological features. This human liver micro-organoid co-culture reproduces alcohol-induced hepatic BMP dysregulation and downstream bone defects, offering an organoid-centric, microengineered platform for mechanistic studies and BMP-targeted therapeutic screening in HOD. Full article

(This article belongs to the Special Issue Recent Advances in Microfluidics and Organoids for Biomedical Applications)

► Show Figures

Figure 1

13 pages, 1759 KB

Open AccessArticle

The Highly Selective 5-HT_2B Receptor Antagonist MW073 Mitigates Aggressive Behavior in an Alzheimer’s Disease Mouse Model

by Erica Acquarone, Saktimayee M. Roy, Agnieszka Staniszewski, Daniel Martin Watterson and Ottavio Arancio

Cells 2026, 15(3), 273; https://doi.org/10.3390/cells15030273 - 1 Feb 2026

Abstract

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients and [...] Read more.

Background: Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder and the leading cause of dementia worldwide. Progressive synaptic dysfunction underlies declines in cognition, daily functioning, and the development of neuropsychiatric syndromes. Neuropsychiatric syndromes that include agitation and aggression affect 40–60% of patients and represent a major source of caregiver burden. Serotonin 5-HT_2B receptor levels are increased in the AD patient brain, and thus, treatment of AD animal models with the selective 5-HT_2B receptor antagonist MW073 in prevention or disease stage paradigms attenuates Aβ- or tau-induced dysfunction. Methods: We investigated the effects of MW073 treatment on the aggressive behavior of Tg2576 mice in a resident–intruder assay. Results: MW073 treatment significantly reduced aggressive behavior in male Tg2576 mice. Conclusions: MW073 efficacy in treating aggression in Tg2576 mice implicates 5-HT_2B receptor-mediated signaling in AD neuropsychiatric symptoms as well as cognitive and behavioral dysfunction. Full article

(This article belongs to the Special Issue Recent Advances in the Understanding of Neuropsychiatric Illnesses)

► Show Figures

Figure 1

20 pages, 3919 KB

Open AccessArticle

Dendrimer-Conjugated Glutamine Antagonist, D-TTM020, Ameliorates Brain Immune Dysregulation and Improves Neurobehavioral Deficits in the Mecp2-Deficient Mouse Model

by Preeti Vyas, Elizabeth Smith Khoury, Nirnath Sah, Anjali Sharma, Javier Allende Labastida, Elizabeth L. Wilkinson, Kathleen Lac, Nerketa N. L. Damiba, Amanda Fowler, Jinhuan Liu, Ashley Bedner, Pavel Majer, Tomás Tichý, Ajit G. Thomas, Rana Rais, Barbara S. Slusher, Rangaramanujam M. Kannan and Sujatha Kannan

Cells 2026, 15(3), 272; https://doi.org/10.3390/cells15030272 - 1 Feb 2026

Abstract

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine [...] Read more.

Rett Syndrome (RTT) is a neurodevelopmental disorder characterized by mutations in the MeCP2 gene, predominantly affecting females. Recent work with MeCP2-deficient mouse models showed a significant role in glutamatergic transmission, specifically microglia-produced glutamate and glutaminase upregulation, in RTT pathology. The glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) is a potent glutaminase inhibitor; however, its use is limited due to systemic toxicities arising from its non-specific inhibition of glutamine-utilizing reactions. In this work, we determined whether dendrimer conjugation of a DON analog, TTM020 (or D-TTM020), results in targeted microglial glutaminase inhibition and behavioral changes in Mecp2 KO and heterozygous mice upon systemic administration. D-TTM020 at 1 mg/kg (drug basis) selectively and significantly inhibits glutaminase enzyme activity in the microglia of Mecp2 KO mice. Biweekly systemic treatment with 1 mg/kg of D-TTM020 improved the neurobehavioral phenotype in symptomatic Mecp2 KO and het mice. D-TTM020 also restored long-term retrieval of conditioned fear memory and improved cue responses during fear extinction after 8 weeks of treatment in symptomatic Mecp2 het mice. Our data indicate that selectively targeting glutamine metabolism in dysregulated glia using dendrimers represents a promising strategy that may offer a therapeutic approach for addressing glutamate dysregulation in RTT. Full article

(This article belongs to the Section Cellular Neuroscience)

► Show Figures

Figure 1

22 pages, 1507 KB

Open AccessReview

Stress-Driven Selective Neuronal Vulnerability in Charcot–Marie–Tooth Disease: From Prodromal Pathology to Therapeutic Implications

by Xianchao Pan, Jiming Xie, Zhiyu Li, Yuemeng Xiang, Yongzhen Yu, Qianqian Cai, Haidong Xu, Ying Wan and Juan Xing

Cells 2026, 15(3), 271; https://doi.org/10.3390/cells15030271 - 31 Jan 2026

Abstract

Charcot–Marie–Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor [...] Read more.

Charcot–Marie–Tooth (CMT) disease represents the most prevalent inherited peripheral neuropathy with a broad range of clinical manifestations, inheritance patterns, and causative genes. The primary pathological hallmark is progressive degeneration, predominantly affecting sensory and motor neurons, leading to prominent sensory deficits and progressive motor impairments. While neuropathy-causing mutations in the ubiquitously expressed small heat shock protein HSPB1 account for a subset of axonal CMT cases, the mechanisms underlying the selective vulnerability of peripheral neurons remain poorly understood. In this review, we synthesize emerging evidence to reframe HSPB1-related CMT as a prototypical gene–environment interaction disorder. The unique anatomical exposure and high metabolic demands of the peripheral nervous system (PNS) render it particularly vulnerable to HSPB1 mutation-mediated homeostatic collapse, which manifests through three interconnected pathological axes: proteostatic disturbance, cytoskeletal dysregulation, and mitochondrial dysfunction. Crucially, these deficits converge to impair the stress adaptability of peripheral neurons, creating a maladaptive feedback loop wherein environmental stressors exacerbate intrinsic vulnerabilities. We further propose a phase-specific therapeutic framework that prioritizes early intervention during the clinically silent yet biologically active prodromal stage, when targeted modulation of the HSPB1 chaperone interactome and remodeling neural homeostasis may forestall neurodegeneration. This therapeutic paradigm shift from symptomatic management to preclinical neuroprotection underscores the imperative for precision medicine approaches in future CMT intervention. Full article

(This article belongs to the Special Issue Mechanisms, Biomarkers, and Therapeutics of Neurodegeneration)

21 pages, 2340 KB

Open AccessArticle

WWOX Induction Promotes Bcl-X_L and Mcl-1 Degradation Through a Lysosomal Pathway upon Stress Responses

by Yu-Han Su, Wei Chiang, Yi-Yu Wang, Yi-Hsi Kung, Pai-Shan Cheng, Tsung-Hao Chang, Nan-Shan Chang, Feng-Jie Lai and Li-Jin Hsu

Cells 2026, 15(3), 270; https://doi.org/10.3390/cells15030270 - 31 Jan 2026

Abstract

The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We [...] Read more.

The human WWOX gene resides on a common fragile site and is frequently deleted or altered during DNA replication. WWOX mutations are associated with various human diseases, including cancer, neurodegeneration, and developmental deficits. However, the regulation of WWOX expression remains largely unclear. We demonstrated that stress responses, including serum deprivation, oxidative stress, and anticancer drug treatment, increase WWOX expression in human SCC-15 cells and wild-type mouse embryonic fibroblasts (MEFs) through transcriptional activation. Serum deprivation induces higher levels of reactive oxygen species and cell death in Wwox^+/+ than Wwox^−/− MEFs. Anti-apoptotic Bcl-2 family proteins regulate mitochondrial homeostasis and prevent serum deprivation-induced oxidative stress and cell death. Our results showed that serum starvation decreases protein expression levels of Bcl-X_L and Mcl-1 in Wwox^+/+ but not in Wwox^−/− MEFs. Serum starvation also fails to downregulate Bcl-X_L and Mcl-1 protein expression in WWOX-knockdown SCC-15 cells. Replenishment of ectopic WWOX induces downregulation of Bcl-X_L and Mcl-1 protein levels in Wwox^−/− MEFs after serum starvation. We determined that WWOX-mediated downregulation of Bcl-XL and Mcl-1 is accomplished through a lysosome-dependent protein degradation pathway. Moreover, a decline in reactive oxygen species generation by pretreatment of Wwox^+/+ MEFs with an antioxidant N-acetyl-L-cysteine leads to decreased WWOX induction upon serum starvation. Taken together, our results suggest that stress stimuli trigger WWOX induction by elevating the production of reactive oxygen species in cells, which promotes the degradation of Bcl-XL and Mcl-1 proteins via a lysosome-mediated pathway, thereby further aggravating oxidative stress and cell death. Full article

(This article belongs to the Special Issue The Role of Cell Signaling Pathway Starvation Therapy for Cancer)

Journal Description

Cells

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI