Search Results (11,379)

Background/Objectives: The fundamental classification based on white, brown, pink, and beige adipose tissue morphology together with fat vacuole content released into the tumor microenvironment incompletely defines breast cancer-associated adipose tissue (BCAAT) heterogeneity and does not sufficiently explain its controversial impact on invasion, recurrence, or survival in breast cancer (BC). We aim to expand BCAAT characterization by systematically evaluating stromal cellular elements within peritumoral adipose tissue, including CD34-positive fibroblasts, smooth muscle actin (SMA)-positive myofibroblasts, inflammatory cells, and microvascular structures to define distinct BCAAT subgroups. Methods: CD34 and smooth muscle actin (SMA) double immunohistochemistry was performed on 109 BC tissue specimens from patients aged 35 to 79 years old, followed by microscopic evaluation of cellular and vascular components inside peritumor adipose tissue. Microscopic findings were then correlated to age, body mass index (BMI), lymphovascular (LVI) and perineural invasion (PnI), recurrence (R), and tertiary lymphoid structures (TLSs). Results: Four BCAAT subtypes have been identified as fibroblast-rich (F^Rich_BCAAT), myofibroblast-rich (MyoF^Rich_BCAAT), vascular-rich (V^Rich_BCAAT), and mixed-vascular and inflammatory-rich (VI^Rich_BCAAT). The F^Rich_BCAAT subtype predominates for the age subgroup 35 to 49 years old and is a significantly worse prognostic factor for survival (p = 0.022). For the age subgroup of 50 to 69 years old, the VI^Rich_BCAAT subtype significantly influences PnI (p = 0.05) but not survival (Log-rank test, z = 0.57, p = 0.57). V^Rich_BCAAT was significantly impactful for BC patient survival aged 70 to 75 years old (p = 0.043). BMI did not correlate with any of the BCAAT subtypes but was strongly correlated with prognostic markers for each BCAAT subtype. Conclusions: Based on immunohistochemically detected cellular and vascular components, four microscopic BCAAT subtypes were identified. Three of four BCCAT subtypes specifically affect BC patient prognosis and survival depending on age. Full article

The mammalian heart rapidly loses regenerative capacity after birth and responds to myocardial infarction (MI) with scar formation and development of interstitial fibrosis. Cardiac fibroblasts orchestrate extracellular matrix (ECM) remodeling and cell–cell communication during development and injury; however, how fibroblast heterogeneity and fibroblast communication networks differ between regenerative neonatal and non-regenerative adult hearts remains incompletely defined. We performed scRNA-seq analysis on metabolically active CD45⁻/CD31⁻ nonmyocyte cells from the left ventricles of normal neonatal (P3) and adult (P84) mice to probe heterogeneity in a cardiac fibroblast-enriched population. We identified five transcriptionally distinct cardiac fibroblast subclusters (CF0-CF4) demonstrating different distributions across ages, including an adult-enriched immune/complement-associated program (CF0); an ECM structural-associated program present across ages (CF1); and neonatal-enriched contractile/ECM-remodeling (CF2), Wnt-modulating matrix-regulatory (CF3), and proliferative (CF4) programs. Matrisome category scoring revealed age-dependent divergence in ECM programs: neonatal fibroblasts showed higher enrichment of core matrisome components (particularly collagens and proteoglycans), whereas adult fibroblasts were relatively enriched for matrisome-associated categories, including ECM regulators and secreted factors. Ligand–receptor inference using CellChat demonstrated a broad reduction in fibroblast–fibroblast interaction strength and information flow in adult networks, and adult-enriched signaling was dominated by immune/chemotactic pathways. Finally, projection of subcluster marker programs onto an independent bulk RNA-seq dataset of cardiac fibroblasts 3 days after MI revealed that adult injury partially recapitulates neonatal-associated programs, including activation of the contractile/ECM-remodeling program (CF2) and robust induction of a cell-cycle-associated program (CF4), but lacks an additional neonatal-specific injury program associated with the Wnt-modulating subset (CF3), which was weakly induced or absent in adults. This cardiac fibroblast-enriched single-cell study defines age-dependent fibroblast states, ECM specialization, and communication network architecture that distinguish regenerative neonatal from non-regenerative adult hearts. It also provides a framework to interpret divergent stromal responses after MI and to prioritize fibroblast programs for regenerative and anti-fibrotic strategies. Full article

Background/Objectives: Lafora disease is a fatal and progressive neurodegenerative disorder characterized by the accumulation of insoluble polyglucosan inclusions, known as Lafora bodies, due to impaired glycogen metabolism. Therapeutic strategies aimed at reducing intracellular glycogen accumulation represent a promising approach to mitigating disease progression. This study aimed to evaluate the feasibility of promoting Lafora body degradation by increasing the protein levels of human pancreatic amylase, a glycogen-degrading enzyme, through the SINEUP approach. Methods: Two SINEUP constructs specifically targeting human pancreatic amylase were designed and tested in continuous tumor-derived cell lines of central nervous system origin, as well as in primary fibroblasts obtained from a patient with Lafora disease. Human pancreatic amylase protein and mRNA levels were assessed to determine the specificity of SINEUP-mediated regulation. Enzymatic activity assays were performed to evaluate functional protein upregulation, and intracellular glycogen content was measured in patient-derived fibroblasts. Results: Both SINEUP constructs significantly increased human pancreatic amylase protein expression without affecting mRNA levels, confirming a post-transcriptional mechanism of action. The elevated protein levels were associated with a significant increase in enzymatic activity. In primary fibroblasts derived from a Lafora disease patient, enhanced amylase expression correlated with a marked reduction in intracellular glycogen content. Conclusions: These findings provide proof of concept that SINEUP-mediated upregulation of glycogen-degrading enzymes may represent a viable therapeutic strategy to counteract Lafora body accumulation. Further studies are warranted to assess the efficacy, safety, and translational potential of this approach, particularly in relevant animal models of Lafora disease. Full article

Background: Keloid scarring is a fibroproliferative disorder driven by a complex interplay of genetic, epigenetic, and environmental factors, resulting in significant cosmetic and functional impairment. Despite its high prevalence in African, Asian, and Hispanic populations, the molecular mechanisms underlying ancestry-dependent susceptibility remain incompletely understood. Methods: This narrative review synthesizes current genomic, epigenetic, and multi-omic evidence related to keloid scarring. Relevant literature was identified through a targeted, structured, non-systematic search of PubMed, Scopus, Web of Science, SciELO, and Google Scholar up to August 2025, focusing on genetic susceptibility loci, epigenetic regulation, and ancestry-related differences. PRISMA-ScR guidelines were used as a reporting framework to enhance transparency, without implying a formal systematic review methodology. Results: This synthesis identifies recurrent susceptibility loci at 1q41, 3q22.3, and 15q21.3 across multiple populations. Variants in NEDD4 and regulatory regions near BMP2 emerge as key modulators of profibrotic signaling pathways, including TGF-β/SMAD and NF-κB. Additionally, epigenetic reprogramming and long non-coding RNA networks, such as CACNA1G-AS1, appear to sustain fibroblast hyperactivation. A persistent limitation is the marked underrepresentation of Latin American populations in current genomic studies. Conclusions: Integrating ancestry-specific genomic variation with epigenetic markers is essential for advancing precision diagnostic and therapeutic strategies in keloid scarring. Future research should prioritize diverse, multicenter cohorts and integrative multi-omics approaches to improve risk stratification and enable targeted interventions for this disfiguring condition. Full article

Chemokine CXCL1, also known as Gro-α and MGSA, a ligand of CXCR2, is the best-known CXC chemokine in cancer processes, after CXCL8/IL-8 and CXCL12/SDF-1. This paper is the first review on the role of CXCL1 in general molecular processes associated with cancer. It provides a comprehensive overview that allows for an in-depth understanding of the importance of CXCL1 in tumor-related processes. In this review, however, we did not address the clinical aspects of CXCL1, as these were discussed in our previous review articles. The present paper focuses on the involvement of CXCL1 in cancer processes such as proliferation, cancer stem cell (CSC) function, senescence, angiogenesis, lymphangiogenesis, migration and metastasis, and effects on tumor-associated cells such as neutrophils, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs). It also describes the significance of CXCL1 in cancer-associated diseases such as cancer cachexia, cancer-associated immunodeficiency, neuroinflammatory-mediated affective-like behaviors, bone cancer pain, and acute kidney injury. We also present the effects of obesity on CXCL1-related cancer processes. Full article

MicroRNAs (miRNAs) are small non-coding RNAs that play central roles in post-transcriptional gene regulation and cellular homeostasis maintenance. Dysregulation of miRNA expression is increasingly recognized as a key contributor to tissue injury during the acute phase and to disease progression in the chronic phase. Chronic kidney disease (CKD) commonly progresses and ultimately leads to kidney failure through interstitial fibrosis, which is the final common pathway of CKD progression. Interstitial fibrosis is driven not only by fibroblast activation but also by phenotypic transitions in injured tubular epithelial cells, infiltrating macrophages, and peritubular capillary cells. These multifaceted cellular pathways induce and exacerbate interstitial fibrosis, and several miRNAs have been identified as important regulators of these pathways. In addition to fibrotic pathophysiological features, disease-specific dysregulation of miRNAs has been increasingly detected in various causes of CKD, including diabetic kidney disease, chronic glomerulonephritis, and nephrosclerosis. In this review, we provide an integrated overview of miRNA-mediated regulation in CKD, with particular emphasis on cell lineage functions within fibrotic pathways and disease-specific roles. Finally, we discuss the emerging potential of miRNAs as biomarkers and therapeutic targets for CKD and highlight future research directions. Full article

Cellular senescence of dermal fibroblasts is a central mechanism underlying skin aging and is closely linked to oxidative imbalance and mitochondrial dysfunction. In this study, we investigated the senotherapeutic effects of polyphenol-rich extracts obtained from peel and flesh of Malus pumila Mill. cv. Annurca at different ripening stages. Senescence was induced in human dermal fibroblasts by oxidative stress, and the biological activity of unripe and ripe apple extracts was comparatively evaluated. The effects of the treatments were assessed by analyzing cell viability, apoptotic response, oxidative stress levels, mitochondrial functionality, and established molecular and functional markers of cellular senescence. All extracts were well tolerated by young fibroblasts and selectively promoted apoptosis in senescent cells. However, marked differences in biological activity were observed depending on fruit tissue and ripening stage. Unripe peel extract consistently reduced senescence-associated markers, attenuated oxidative stress, and restored mitochondrial homeostasis, indicating a combined senomorphic and senolytic activity. In contrast, ripe peel extract displayed a predominantly senolytic profile associated with increased oxidative stress, while flesh-derived extracts exerted weaker or incomplete effects on senescence pathways. These results demonstrate that Annurca apple polyphenols modulate cellular senescence depending on fruit part and ripening stage. Peel extracts, particularly from unripe fruits, represent potent and sustainable natural senotherapeutics, highlighting the potential of agro-food by-products for anti-aging and skin rejuvenation applications. Full article

Colorectal cancer (CRC) is still a leading cause of cancer-related death worldwide, and often, conventional chemotherapeutics exhibit limited efficacy. The hydroalcoholic leaf extract of Cynara cardunculus subsp. cardunculus (wild artichoke) was investigated for its anticancer potential in CRC and effects on enteric pathogens. Nine phenolic compounds were identified by high-performance liquid chromatography with diode-array detection (HPLC-DAD), and spectrophotometric analyses were applied for total phenolic (TPC: 178.33 mg GAE/g) and total flavonoid (TFC: 52.21 mg CE/g) content quantification. The extract exhibited good antioxidant activity on DPPH (IC₅₀: 21.35 μg/mL), ^−•O₂ (IC₅₀: 1.56 μg/mL), and H₂O₂ (IC₅₀: 314.73 μg/mL) and was found to inhibit the growth of pathogenic enteric bacteria, with Enterococcus faecalis and Staphylococcus aureus being the most sensitive. In CaCo-2 CRC cells, the extract induced a concentration-dependent cytotoxicity (IC₅₀: 13.07 μg/mL at 24 h) through increased production of reactive oxygen species (ROS), upregulation of Nrf2, and induction of apoptosis, as evidenced by elevated p53, Bax, cytochrome c, and caspase-3 levels. No necrosis, measured by lactate dehydrogenase (LDH) release, or toxicity to HFF-1 normal fibroblasts was observed at concentrations up to 50 μg/mL. Additionally, CCE demonstrated synergistic effects with 5-FU (combination index < 0.8). This evidence suggests that CCE exhibits selective antitumor activity and chemosensitizing properties, supporting its possible development as an adjunctive agent in CRC therapy. Full article

Background/Objectives: Wound repair-associated processes and the antioxidant properties of natural products play critical roles in skin wound healing and barrier restoration. Wound healing is a complex process characterized by a series of interconnected events that facilitate the self-repair of the skin following injury. Methods: This study aimed to evaluate the effects of Quercus acuta acorn bran extract (QAABE) on wound healing using human dermal fibroblast (HDF) cell cultures treated with QAABE. Additionally, in vivo experiments were conducted using a mouse model of skin injury to assess the wound-healing potential of the extract. Results: The results indicated that QAABE enhanced wound healing in vitro by upregulating extracellular matrix-related markers, including vimentin, Col1a1, Col3a1, endothelin, fibronectin, and VEGF at the mRNA level, and increasing the protein expression of vimentin, COL1A1, endothelin, and α-SMA. QAABE also exhibited reactive oxygen species (ROS)-scavenging activity. In the mouse skin injury model, QAABE treatment accelerated wound closure and was associated with reduced inflammatory responses. Conclusions: These findings suggest that QAABE may promote wound-healing-related responses in both in vitro and in vivo models, supporting its potential as a candidate for further investigation in wound-healing research. Full article

Wounds caused by Vibrio vulnificus (V. vulnificus) infection often exhibit delayed healing and are prone to complications, making them a significant challenge in clinical treatment. Current conventional treatments, such as antibiotics and gauze dressings, have limited effectiveness. To address this, this study developed a multifunctional fiber membrane using electrospinning technology. Micron- or nano-sized Haliotidis Concha (HC) and eugenol (Eu) were loaded onto the membrane to promote healing in V. vulnificus-infected wounds. The prepared fiber membranes exhibited diameters of approximately 0.35 ± 0.01 μm. Membranes loaded with nano-HC demonstrated significant antibacterial efficacy, achieving a 96.2% inhibition rate against V. vulnificus, which was markedly superior to the micron-HC group (p < 0.05). Notably, the nano-HC/Eu membranes exhibited exceptionally high flexibility with an elongation at break of 878.1 ± 35.3%, while maintaining a tensile strength of approximately 2.2 MPa. Furthermore, these membranes exhibited excellent biocompatibility, with cell viability exceeding 85% for fibroblasts, and demonstrated good hemocompatibility. They also effectively promoted cell migration, indicating their potential as wound scaffold materials. In a V. vulnificus-infected skin wound model, the nano-HC/Eu fiber membrane accelerated collagen deposition and promoted wound healing, achieving a wound closure rate of 94.7 ± 1.1% on day 15. In summary, this study developed a multifunctional fiber membrane with antibacterial, antioxidant, and wound healing properties, offering a novel dressing for treating V. vulnificus infections. Full article

Objective: The biocompatibility of adhesive systems is essential for the long-term success of restorative dental procedures due to their close proximity to dentin and pulpal tissues. This study aimed to evaluate the cytotoxic effects of adhesive systems with different pH values on L929 mouse fibroblast cells under in vitro conditions. Materials and Methods: Four commercially available adhesive systems with different pH values—All-Bond Universal, G-Premio Bond, Tokuyama Bond Force II, and Clearfil Universal Bond Quick—were evaluated. Cytotoxicity was assessed using the MTT assay at four different concentrations (0.1%, 0.01%, 0.001%, and 0.0001%) and three incubation periods (24, 48, and 72 h). Cell viability data were analyzed using two-way analysis of variance followed by Bonferroni post hoc tests. Cytotoxicity was interpreted according to ISO 10993-5 criteria. Results: All adhesive systems exhibited concentration-dependent cytotoxicity, with significant reductions in cell viability observed only at the highest concentration (0.1%). At lower concentrations, no cytotoxic effects were detected. Despite having the highest pH value, All-Bond Universal consistently demonstrated the lowest cell viability. In contrast, Tokuyama Bond Force II showed the most favorable cytocompatibility profile, with relatively higher cell viability values over time. Morphological analysis supported the quantitative findings, revealing pronounced cellular alterations at high concentrations and preserved fibroblastic morphology at lower concentrations. Conclusions: adhesive systems demonstrate cytotoxic effects in a concentration-dependent manner, and pH alone is insufficient to predict their biocompatibility. Monomer composition and formulation characteristics appear to play a more critical role in determining cytotoxic behavior. These findings emphasize the importance of appropriate adhesive handling and isolation techniques to minimize tissue exposure and enhance clinical safety. Full article

Background/Objectives: High recurrence rates and intensive lifelong surveillance make bladder cancer among the costliest malignancies to treat. Although Bacillus Calmette–Guérin (BCG) immunotherapy is the standard treatment for high-risk non-muscle-invasive bladder cancer (NMIBC), up to 50% of patients fail to respond, and predictive biomarkers are lacking. Molecular profiling has established three BCG response subtypes (BRS1–3), with BRS3 characterized by an immunosuppressive, BCG-resistant phenotype; however, these features have not been validated at single-cell spatial resolution. Methods: We applied imaging mass cytometry (IMC) to 82 BCG-treated high-risk NMIBC samples and performed (i) single-cell IMC with unsupervised clustering to identify phenotypic cell clusters and quantify cluster abundances and (ii) a convolutional neural network-based gated attention multiple instance learning model trained on IMC images (IMC-GA-MIL) to predict BCG response. Cluster abundances were summarized using II (immune composition within the immune compartment), TT (tumor phenotypic composition), and IT (immune/stromal abundance relative to tumor cells) indices. Results: Single-cell IMC identified 18 distinct phenotypic cell clusters. In BCG responders, immune cells localized within the tumor compartment were enriched and independently protective (HR 0.67, 95% CI 0.49–0.92). BCG nonresponse was associated with a higher abundance of fibroblast-dominant clusters relative to tumor cells (IT index). Plasma cell-dominant clusters were the strongest predictors of progression (II index HR 2.28, 95% CI 1.37–3.79; IT index HR 1.25, 95% CI 1.06–1.48). The IMC-GA-MIL model predicted BCG response with 90% accuracy (9/10) and identified myeloid- and T-cell-associated marker patterns involving CD14, CD11b, CD68, CD8, and FOXP3 as the most informative contributors. Conclusions: Spatial single-cell profiling and IMC-GA-MIL identify spatial immune and stromal features associated with BCG failure. However, findings from both analyses should be considered exploratory and will require validation in larger, independent cohorts. Full article

Collagen is a major extracellular-matrix protein widely used in regenerative medicine, yet conventional terrestrial sources raise biosafety and acceptability concerns, motivating the search for marine alternatives. This study evaluates the jellyfish Rhizostoma pulmo (R. pulmo) from the Azov Sea as a sustainable collagen source and assesses its suitability for biomedical materials. Acid-soluble collagen was extracted using 0.5 M acetic acid and purified by salt precipitation and dialysis, followed by physicochemical/structural characterization (sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE), Limulus amebocyte lysate (LAL) endotoxin testing, transmission electron microscopy (TEM), and immunofluorescence with type I collagen antibodies) and biological evaluation in vitro (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity on MRC5 fibroblasts; adhesion and proliferation assays on HeLa cells). The extracted collagen showed a high yield (~26.2%), a type I-like electrophoretic profile with α-, β-, and γ-components, fibrillar ultrastructure by TEM, and positive type I collagen immunoreactivity; endotoxin levels were low (0.461 EU/µL), and no cytotoxicity was detected under the tested conditions. Porous collagen sponges/scaffolds were fabricated by lyophilization, displaying interconnected pores with an average size of ~80 µm and pH-dependent swelling, and they supported 3D cell growth and tumor-cell dissemination in an in vitro breast carcinoma scaffold model. Overall, Azov Sea R. pulmo collagen demonstrates promising structural quality, low endotoxin burden, and cytocompatibility, supporting its potential as a marine biomaterial for sponge/scaffold-based tissue engineering and wound-related applications. Full article

From an epidemiological perspective, polymorphous low-grade neuroepithelial tumor (PLNTY) represents a small proportion of brain tumors encountered in epilepsy surgery series. Their rarity and relatively recent recognition likely contribute to underdiagnosis and poor prognosis. In terms of histopathological features, they are similar to oligodendrogliomas. Molecular analyses can be used to show the fusion between fibroblast growth factor receptor (FGFR3) and transforming acidic coiled coil (TACC) proteins, which most commonly results in progression towards glioblastoma (GBM). We report a case of a 62-year-old man who underwent left frontal craniotomy to remove a frontal mass. Histologically, the glial lesion consisted of elements associated with oligodendroglia-like features. Immunohistochemistry was positive for glial fibrillary acidic protein (GFAP), oligodendrocyte transcription factor 2 (OLIG2), and α-thalassemia X-linked mental retardation syndrome (ATRX) nuclear expression, but negative for isocitrate dehydrogenase 1 (IDH1) and BRAF-V600E. Next-generation sequencing showed the FGFR-TACC3 fusion, and taken together, these findings supported the final diagnosis of PLNTY. During follow-up, the patient underwent a second neurosurgery, where histological evaluation indicated a GMB. This article presents clinical and radiological data, morphology, immunohistochemistry, molecular features, and treatment to enhance the clinical and pathological understanding of PLNTY with FGFR3-TACC3 fusion for all professionals involved in medical decisions. Full article

Background: Triple-negative breast cancer lacks established targeted therapies, and only a subset of patients achieves a pathologic complete response to neoadjuvant chemotherapy. We aimed to integrate bulk cohorts with an exploratory single-cell multi-omic dataset from only five patients to identify tumor and immune-related features associated with chemotherapy response. Methods: Bulk analyses were performed in two public breast cancer cohorts (GSE76275 and GSE25065) to compare triple-negative versus non-triple-negative tumors and to relate pretreatment transcriptional and inferred immune infiltration patterns to neoadjuvant chemotherapy response. Separately, in a hypothesis-generating single-cell cohort of five triple-negative breast cancers (n = 5; four responders, one non-responder), we performed single-cell RNA sequencing, T cell and B cell receptor sequencing, single-cell ATAC sequencing, and glycosylation tag profiling. Results: In bulk data, triple-negative tumors showed a loss of luminal estrogen receptor-associated programs, higher proliferation, and CIBERSORT-estimated enrichment of myeloid-associated immune fractions compared with non-triple-negative tumors. Chemotherapy response was associated with modest transcriptional shifts and inferred immune composition differences in triple-negative tumors and more pronounced epithelial, stromal, and inflamed immune changes in non-triple-negative disease. Single-cell data suggested that responder tumors were enriched for T and natural killer cells, antigen-presenting myeloid cells, expanded and diverse T and B cell clonotypes, and immune-associated glycosylation signals, whereas the non-responder sample was dominated by epithelial and fibroblast compartments with secretory, adhesion, and potential immune evasion programs. Checkpoint-related analyses reflected expression patterns and predicted ligand–receptor communication, nominating TIGIT–NECTIN2 as a candidate axis for further investigation. Conclusions: Integrating public bulk cohorts with exploratory single-cell multi-omics supports a model in which chemotherapy sensitivity in triple-negative breast cancer is linked to inflamed, antigen-presenting microenvironments and adaptable antitumor immunity, whereas resistance is associated with stromal and tumor dominance. These candidate biomarkers and pathways require validation in larger independent cohorts, and clinical translation is premature given the exploratory single-cell cohort. Full article