Search Results (2,497)

Alzheimer’s disease (AD) is marked by cognitive decline, and also by retinal degeneration. Having in mind that docosahexaenoic acid (DHA, 22:6n − 3) is a safe, low-cost, and pivotal fatty acid for brain health and sustained cognitive function, this study exploits environmentally friendly non-fish sources as potential dietary supplements enriched with DHA to prevent or reverse AD. Forty 5xFAD transgenic male mice, aged five weeks old, were randomly distributed by five body weight-matched dietary groups (with eight animals each) and fed isocaloric diets based on the AIN-93M standard formulation for rodents for 6 months. Except for the control feed (without supplementation), each diet contained a modified lipidic fraction supplemented with 2% of the following: (1) linseed oil (LSO, rich in alpha-linolenic acid (ALA, 18:3n − 3)); (2) cod liver oil (fish oil, FO, rich in both DHA and eicosapentaenoic acid (EPA, 20:5n − 3)); (3) Schizochytrium sp. microalga oil (Schizo, with 40% of DHA); and (4) commercial DHASCO (DHASCO, with 70% of DHA). The aim of this study was to measure retinal neural layer thickness, calculate ganglion cell layer (GCL) density, and assess retinal injury by means of immunohistochemical staining for β-amyloid plaques deposition, TAU protein levels, and IBA1, as hallmark features of AD progression, in order to elucidate the effects of different dietary DHA treatments in Alzheimer’s retinas. Although no statistical differences were observed across retinal layer thicknesses depending on the diet (p > 0.05), there was a consistent pattern for slightly increased retinal thickness in 5xFAD mice fed fish oil relative to the others for the measurement of total layers, in general and for the inner segment/outer segment layer, the outer nuclear layer, the outer plexiform layer, the inner nuclear layer, and the inner plexiform layer, in particular. The ganglion cell layer (GCL) density was increased in 5xFAD mice fed the DHASCO oil diet relative to the control (p < 0.05), suggesting a benefit of DHA supplementation on the number of viable ganglion cells. No positive staining was observed for β-amyloid plaques deposition or the neuroinflammatory marker, IBA1, corroborating previous findings in human AD retinas. Conversely, the internal retinal layers showed intense TAU immunostaining. Immnunostained TAU area was significantly reduced in 5xFAD mice fed a fish oil diet compared to control (p < 0.05), although the number of TAU-positive cells did not differ across diets (p > 0.05). The retinal protected integrity derived from the benefits of DHA supplementation found, either from fish oil or DHASCO oil, underscores the potential of retinal biomarkers as non-invasive indicators of cognitive decline and overall brain health, opening new avenues for investigating AD pathophysiology in the retina. Full article

Background: Ovarian cancer (OC) remains one of the most lethal gynecologic malignancies due to its often-late diagnosis and complex molecular heterogeneity. Understanding the metabolic alterations in OC can provide insights into its pathophysiology and potential therapeutic targets. This study aimed to explore serum metabolomic profiles and their correlation with clinical and pathological features in OC patients. Materials and Methods: Thirty serum samples were collected from patients diagnosed with ovarian tumors (OTs) (n = 24 malignant, n = 6 benign) and undergoing treatment at Careggi University Hospital. Additionally, 47 samples were obtained from age-matched healthy female donors. Serum samples underwent processing and analysis using an H-NMR (Nuclear Magnetic Resonance) platform to identify a panel of metabolites. Correlation analysis between the metabolomic data and clinical parameters was performed using R software (v.4.4.0). Results: Differential metabolomic profiling showed a significant upregulation of metabolites associated with the purine salvage pathway (i.e., hypoxanthine and inosine) and the ketone bodies axis (i.e., acetone, 3-hydroxybutyrate, and acetate) in samples from ovarian tumor (OT) patients compared to healthy donors. Within malignant OC samples, metabolomic profiles significantly correlated with BRCA1/2 mutation status (BRCA1/2-mutated vs. wild-type) and homologous recombination deficiency (HRD) status. Conclusions: The analysis revealed significant variation in specific metabolites such as betaine, creatinine, carnitine, glycerol, and mannose; notably, a downregulation of these metabolites was observed in HRD-positive patients. The study identifies significant metabolomic alterations in OC, implicating pathways such as purine salvage and ketone bodies. Intriguingly, consistent variation in specific metabolites across BRCA/HRD phenotypes underscores their potential as OC biomarkers. Further research is needed to validate these findings and explore their prognostic and therapeutic implications. Full article

Lentigo maligna (LM) is a melanoma in situ with high cumulative sun damage. Histological evaluation of resection margins is difficult and time-consuming. Melanocyte density (MD) is a suitable, quantifiable, and reproducible diagnostic criterion. In this retrospective single-centre study, we investigated whether an artificial intelligence (AI) tool can support the assessment of LM. Training and evaluation were based on MD in Sox-10-stained digitalised slides. In total, 86 whole slide images (WSIs) from LM patients were annotated and used as a training set. The test set consisted of 177 slides. The tool was trained to detect the epidermis, measure its length, and determine the MD. A cut-off of ≥30 melanocytes per 0.5 mm of epidermis length was defined as positive. Our AI model automatically recognises the epidermis and measures the MD. The model was trained on nuclear immunohistochemical signals and can also be applied to other nuclear stains, such as PRAME or MITF. The WSI is automatically visualised by a three-colour heat map with a subdivision into low, borderline, and high melanocyte density. The cut-offs can be adjusted individually. Compared to manually counted ground truth MD, the AI model achieved high sensitivity (87.84%), specificity (72.82%), and accuracy (79.10%), and an area under the curve (AUC) of 0.818 in the test set. This automated tool can assist (dermato) pathologists by providing a quick overview of the WSI at first glance and making the time-consuming assessment of resection margins more efficient and more reproducible. The AI model can provide significant benefits in the daily routine workflow. Full article

The chromatin remodelling proteins DAXX and ATRX are key regulators of genome stability and epigenetic processes. Alterations in their expression have been associated with tumour stage and prognostic outcomes in various human cancer types, whereas their role in veterinary oncology has received little investigation to date. We analysed canine prostate and urinary bladder samples, including 18 prostate carcinomas (12 adenocarcinomas and 6 prostatic urothelial carcinomas), 10 non-malignant prostate tissues, 22 urinary bladder carcinomas, and 6 non-malignant bladder tissues. Nuclear expression of DAXX and ATRX was assessed using fully quantitative digital immunohistochemistry. Overall, DAXX exhibited consistently higher expression than ATRX across benign and malignant samples from the prostate and bladder. DAXX and ATRX expression demonstrated a positive correlation across all samples (ρ = 0.553, p < 0.05), suggesting coordinated regulation. They displayed organ-specific expression patterns: prostate carcinomas showed increased expression of DAXX compared with non-malignant prostate tissues (p < 0.05). In contrast, in the bladder, expression of DAXX and ATRX declined with increasing tumour grade (p < 0.05). Our findings provide new insights into the potential of DAXX and ATRX as biomarkers, offering new insights into their clinical relevance in dogs. Full article

Background/Objectives: The sequencing of mitochondrial DNA is a valuable tool in forensic genetics, particularly in cases involving degraded samples or those with low nuclear DNA content. In this study, we performed an internal validation for an NGS-based typing of the mitochondrial DNA control region using the Precision ID mtDNA Control Region Panel on the Ion S5^TM sequencer (Thermo Fisher Scientific, Waltham, MA, USA). This validation enhances the scientific robustness, reliability, and judicial admissibility of the results in forensic cases. Methods: Six parameters were evaluated: minimum read depth, sensitivity, repeatability, concordance with Sanger, reproducibility and heteroplasmy detection employing ten negative controls, nine reference samples, a bone sample, and six experimental mixtures. Libraries were prepared using the Ion Chef^TM system, quantified on the Quantstudio^TM 5 Real-Time PCR, sequenced on the Ion GeneStudio^TM S5, and analyzed with Converge^TM software. Results: In this study, we found that a read depth threshold of 100 reads per position, an optimal concentration of 20 pg/µL, and a detection threshold of heteroplasmies of 20% are appropriate to obtain reliable genetic profiles. This supports the application of this method in forensic casework, in which initial concentrations may be around the optimal concentration exposed here due to the provenience of the samples. Conclusions: The results indicate that the NGS platform is suitable for forensic mtDNA analysis, even under low-template conditions, and offers higher sensitivity compared to Sanger sequencing. However, some limitations were observed in the coverage of specific amplicons, the detections of polymorphisms in homopolymeric regions, and in the detection of low-level heteroplasmies. Full article

Bovine endometritis negatively impairs fertility and milk production. Taurine maintains cellular integrity and exerts anti-inflammatory and antioxidant effects. However, whether taurine can treat endometritis remains unclear. This study aimed to investigate taurine’s effect on endometritis and explore its mechanism in vivo. Endometritis models were established in mice via intrauterine lipopolysaccharide (LPS) infusion, followed by 25, 50, and 100 mg/kg taurine treatment. Taurine attenuated inflammation by mitigating histopathological damage, suppressing uterine serum cytokine levels, and preserving tight-junction integrity. It ameliorated oxidative stress by reducing malondialdehyde content, restoring antioxidant activities, and recovering levels of oxidative-stress-related proteins. Apoptosis was alleviated by diminishing the apoptosis ratio and normalizing apoptosis-related proteins. 16S analysis revealed taurine restored uterine microbiota composition by reversing the changes in the abundances of Firmicutes, Bacteroidetes, Nocardioides, Ruminococcus, and Acidibacter. The abundances of Muribacter and Rodentibacter were positively correlated with inflammation. The abundances of Akkermansia and Streptococcus were negatively correlated with inflammation. RNA sequencing showed that the differentially expressed genes were mainly related to immunity. Phosphatidylinositol 3-kinase (PI3K)-protein kinase B (AKT)/mitogen-activated protein kinase (MAPK)/nuclear factor kappa B (NF-κB) signaling pathways were indicated as pivotal mechanisms for taurine’s therapeutic efficacy against endometritis with transcriptomic profiling analysis. This study confirms that taurine alleviates LPS-induced endometritis in mice by modulating PI3K–AKT, MAPK, and NF-κB signaling pathways, indicating its potential as a therapeutic agent for bovine endometritis. Full article

Germanium (Ge) incorporation profoundly modifies the structural and electronic characteristics of carbon fullerenes, giving rise to a diverse landscape of substitutional, exohedral, and endohedral Ge–fullerene architectures. Although experimental studies demonstrate that Ge can be introduced into fullerene matrices through nuclear recoil implantation and arc-discharge synthesis, only exohedral germylated derivatives have been structurally confirmed to date. Substitutional germanium-doped fullerene (Ge-C₆₀) species remain experimentally elusive, with available evidence relying largely on radiochemical signatures and indirect spectroscopic data. In contrast, computational investigations provide a detailed and coherent picture of germanium doping across fullerene sizes, showing that Ge induces significant cage distortion, breaks local symmetry, narrows the highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) gap, and enhances charge localization at the dopant site. These electronic perturbations strongly increase the affinity of Ge-doped fullerenes for external guest molecules, leading to enhanced adsorption energies and distinct optical and transport responses in exohedral complexes. Theoretical studies of endohedral systems further indicate that Ge atoms or small clusters could form stable encapsulated species with unique electronic properties. Collectively, current evidence positions germanium-doped fullerenes as electronically versatile nanostructures with potential applications in sensing, optoelectronics, catalysis, and nanomedicine, while highlighting the need for definitive experimental synthesis and structural validation of substitutional Ge-fullerene derivatives. Full article

The peptidylarginine deiminase (PAD) family includes five isozymes (PAD1–4 and PAD6) with unique tissue distributions and substrate specificities. These enzymes facilitate citrullination, a post-translational modification where positively charged arginine residues are converted into neutral citrulline residues in the presence of calcium ions. This process significantly changes protein properties, affecting molecular interactions, structural stability, and biological functions. Over the past six years (2019–2025), there has been significant progress in understanding PAD activity mechanisms and their therapeutic potential. Recent discoveries include the regulated nuclear translocation of PAD2, PAD4’s specific role in forming cancer extracellular chromatin networks (CECNs), and the development of next-generation inhibitors with greatly improved pharmacological profiles. PAD4 is crucial in forming neutrophil extracellular traps (NETs). Citrullination of histones H3 and H4 by PAD4 destabilizes chromatin, helping release DNA-protein networks as an antibacterial defense. However, excessive NET formation can contribute to autoimmune diseases and thrombosis. Similarly, the bacterial peptidylarginine deiminase from Porphyromonas gingivalis (PPAD)—the only known prokaryotic citrullinating enzyme—plays a key role. Working with R-gingipains, PPAD triggers pathological citrullination of host proteins, leading to immune tolerance breakdown and linking periodontal disease with systemic autoimmune disorders such as rheumatoid arthritis, atherosclerosis, and Alzheimer’s disease. Once thought to be a rare post-translational modification, citrullination is now understood as a vital regulatory mechanism in both normal physiology and disease, involving both internal processes of homeostasis and external mechanisms of bacterial pathogenesis. Full article

The AP2/ERF transcription factor family plays pivotal roles in regulating plant growth, development, and responses to environmental stimuli. In this study, we identified and functionally characterized SlERF.F4, a tomato (Solanum lycopersicum) ERF gene encoding a nuclear-localized protein with a conserved AP2/ERF domain. SlERF.F4 transcript levels were rapidly induced by diverse abiotic stresses and phytohormones, including drought, salinity, temperature extremes, abscisic acid (ABA), and brassinosteroids (BR). Overexpression of SlERF.F4 in tomato resulted in reduced plant height, delayed fruit ripening, and downregulation of key ripening-associated genes (RIN, CNR, E4, E8, and PG). Furthermore, SlERF.F4 transgenic lines exhibited enhanced drought tolerance, characterized by reduced wilting, lower malondialdehyde (MDA) accumulation, and significantly higher survival rates under water-deficit conditions. Collectively, these results indicate that SlERF.F4 functions as a negative regulator of fruit ripening and a positive modulator of drought tolerance, highlighting its potential as a target for tomato genetic improvement. Full article

Background/Objectives: Sirtuin 7 (SIRT7), a nuclear NAD⁺-dependent deacylase, plays multifaceted and sometimes opposing roles in tumorigenesis. By preserving chromatin architecture and genome integrity, SIRT7 protects against malignant transformation; however, once cancer is established, it can either sustain or restrain tumor growth through context-dependent signaling programs, albeit via largely unknown mechanisms. Recent findings have uncovered an additional—and previously underappreciated—dimension: SIRT7’s capacity to modulate anti-cancer immunity. This review revisits the current understanding of SIRT7 in cancer by emphasizing its emerging immunomodulatory functions and influence on the tumor microenvironment. Methods: We conducted a comprehensive literature review up to October 2025 using the PubMed database to identify both tumor-intrinsic and tumor-extrinsic mechanisms linking SIRT7 to anti-cancer immunity and to relate the established molecular functions of SIRT7—such as its roles in metabolism, genome maintenance, and inflammatory regulation—to immune regulation. Results: SIRT7 directly regulates immune checkpoint expression and T cell metabolic fitness, thereby positioning it as a key node connecting tumor-intrinsic programs with immune surveillance. Moreover, by controlling molecular pathways such as metabolism, genomic stability, and inflammatory responses—both within cancer cells and across other components of the tumor microenvironment—SIRT7 may more broadly influence the immune landscape, orchestrating immune evasion or recognition. Conclusions: Deciphering how SIRT7’s tumor-intrinsic and immunomodulatory functions intersect is essential for anticipating the consequences of its pharmacological targeting in cancer. A deeper understanding of this interplay will enable the rational design of combination strategies that integrate SIRT7 modulation with immunotherapy within a precision medicine framework. Full article

The cannabinoid receptor type 2 (CB₂) is increasingly recognized as a crucial regulator of neuroimmune balance in the brain. In addition to its well-established role in immunity, the CB₂ receptor has been identified in specific populations of neurons and glial cells throughout various brain regions, and its expression is dynamically increased during inflammatory and neuropathological conditions, positioning it as a potential non-psychoactive target for modifying neurological diseases. The expression of the CB₂ gene (CNR2) is finely tuned by epigenetic processes, including promoter CpG methylation, histone modifications, and non-coding RNAs, which regulate receptor availability and signaling preferences in response to stress, inflammation, and environmental factors. CB₂ signaling interacts with TRP channels (such as TRPV1), nuclear receptors (PPARγ), and orphan G Protein-Coupled Receptors (GPCRs, including GPR55 and GPR18) within the endocannabinoidome (eCBome), influencing microglial characteristics, cytokine production, and synaptic activity. We review how these interconnected mechanisms affect neurodegenerative and neuropsychiatric disorders, underscore the species- and cell-type-specificities that pose challenges for translation, and explore emerging strategies, including selective agonists, positive allosteric modulators, and biased ligands, that leverage the signaling adaptability of the CB₂ receptor while reducing central effects mediated by the CB₁ receptor. This focus on the neuro-centric perspective repositions the CB₂ receptor as an epigenetically informed, context-dependent hub within the eCBome, making it a promising candidate for precision therapies in conditions featuring neuroinflammation. Full article

Pediatric inflammatory bowel disease (pIBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), involves complex mechanisms that include non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), alongside enzymes regulating serotonin metabolism. Tryptophan hydroxylase 1 (TPH1) and monoamine oxidase A (MAOA) play critical roles in serotonin turnover and may contribute to intestinal inflammation. We investigated the expression of TPH1, MAOA, hsa-miR-194-5p, hsa-miR-1276, and the lncRNA Nuclear Enriched Abundant Transcript 1 (NEAT1) in intestinal tissue biopsies and peripheral blood from pIBD patients and controls. TPH1 was significantly elevated in the inflamed transverse colon (p = 0.034), whereas MAOA was reduced in the ileum (p = 0.041) and descending colon (p = 0.001), with further decreases in inflamed ileum (p < 0.001), ascending (p = 0.008), and descending colon (p = 0.001). Subgroup analysis revealed decreased MAOA in the ascending colon of UC patients (p = 0.011). hsa-miR-194-5p was upregulated in the transverse colon (p = 0.015), inflamed transverse (p = 0.013) and descending colon (p = 0.015), and in blood of UC patients (p = 0.01). NEAT1 expression increased in the ascending colon (p = 0.042) but decreased in the ileum (p = 0.006). Correlation analysis showed strong positive associations between TPH1 and NEAT1 in the ileum (r = 0.945, p < 0.01) and transverse colon (r = 0.609, p < 0.01). These results highlight region-specific dysregulation of serotonin-related genes and ncRNAs in pIBD, with the TPH1/miR-194-5p/NEAT1 axis potentially contributing to disease pathophysiology and warranting further mechanistic investigation. Full article

Plant microRNAs (miRNAs) are endogenous non-coding RNAs (~20–24 nucleotides) that regulate gene expression post-transcriptionally, playing critical roles in plant growth, development, and stress responses. This review systematically examines AI applications in plant miRNA research, tracing evolution from traditional machine learning to deep learning architectures. Plant miRNAs exhibit distinctive features necessitating plant-specific computational approaches: nuclear-localized biogenesis, high target complementarity (>80%), and coding region targeting. These characteristics enable more accurate computational prediction and experimental validation than animal systems. Methodological advances have improved prediction accuracy from ~90% (early SVMs) to >99% (recent deep learning), though metrics reflect different evaluation contexts. We analyze applications across miRNA identification, target prediction with degradome validation, miRNA–lncRNA interactions, and ceRNA networks. Critical assessment reveals that degradome data capture mixed RNA fragments from multiple sources beyond miRNA cleavage, requiring stringent multi-evidence validation. Similarly, fundamental ambiguities in lncRNA definition compound prediction uncertainties. Major challenges include severe data imbalance (positive to negative ratios of 1:100 to 1:10,000), limited cross-species generalization, insufficient model interpretability, and experimental validation bottlenecks. Approximately 75% of plant miRNA families in miRBase v20 lack convincing evidence, underscoring the need for rigorous annotation standards. Future directions encompass multimodal deep learning, explainable AI, spatiotemporal graph neural networks, and ultimately AI-driven de novo miRNA design, though the latter requires substantial advances in both computation and high-throughput validation. This synthesis demonstrates that AI has become indispensable for plant miRNA research, providing essential support for crop improvement while acknowledging persistent challenges demanding continued innovation. Full article

A disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6) is an extracellular matrix (ECM) protease that promotes the invasion of lung adenocarcinoma (LUAD) cells. Herein, we investigate its role in epithelial-mesenchymal transition (EMT), a process that drives metastasis and drug resistance in LUAD. Re-analysis of microarray and RNA sequencing data from LUAD cells revealed that during EMT, TGF-β1 increased ADAMTS6 expression, presumably through the SMAD pathway, as SMAD2 loss completely blocked this effect. Moreover, ADAMTS6 was shown to occupy hub positions within TGF-β1-associated gene networks. Using additional datasets, we found that ADAMTS6 expression increased under other EMT-inducing conditions, including IL-1β induction and acquired gefitinib resistance, but decreased upon knockdown of Twist1, a master regulator of EMT. Knockout of ADAMTS6 repressed colony formation, migration, invasion, and doxorubicin resistance but enhanced cell–ECM adhesion in A549 cells. This effect was mediated by EMT inhibition, evidenced by upregulation of E-cadherin and downregulation of N-cadherin, vimentin, and Twist1, and was accompanied by suppressed nuclear translocation of the NF-κB p65 subunit. Re-analysis of transcriptomic data from patient tumors demonstrated that high ADAMTS6 expression correlated with the expression of EMT markers, further supporting the ADAMTS6–EMT link. Moreover, high ADAMTS6 expression was associated with worse survival prognosis. Overall, ADAMTS6 promotes EMT in LUAD cells and may be considered a marker of this process, as well as a potential therapeutic target for its inhibition. Full article

More than 3 million children are infected with hepatitis C virus (HCV) worldwide. Therapies with direct-acting antivirals (DAAs) are characterized by high efficiency and acceptable tolerability. Rare cases of autoimmune hepatitis (AIH) following HCV elimination have been reported in adults. Here, we present the first pediatric case of AIH after successful treatment with DAAs. A girl, born in 2012, was diagnosed with vertical HCV infection in 2013. In 2023, she was treated with the DAA glecaprevir/pibrentasvir. HCV RNA was undetectable after 4 weeks of treatment and at the end of treatment (EOT). However, at the EOT, the aminotransferase concentration elevated with further increase, despite a confirmed sustained viral response (SVR) 12 weeks after the EOT. Gamma-globulins were elevated, with positive anti-nuclear antibodies (ANA) and anti-liver kidney microsome (LKM) antibodies. Other causes were excluded. Elastography revealed no fibrosis. Aminotransferase levels decreased but did not normalize. A liver biopsy was performed, confirming a diagnosis of AIH. Immunosuppressive therapy with prednisone and azathioprine resulted in normalization of aminotransferase levels, and the titers of both ANA and LKM antibodies decreased. Monitoring aminotransferase levels should not be omitted in patients after successful DAA treatment of HCV infection. Full article