Search Results (659)

Background: idiopathic pulmonary fibrosis (IPF) causes progressive and irreversible changes in the lung parenchyma, leading to respiratory failure. Its pathogenesis involves several damage/repair mechanisms leading to fibrosis, whilst alterations of genes implicated in these processes contribute to the development of the disease. At present, next-generation sequencing (NGS) analyses investigate single-nucleotide or small indel variants, and no evaluation of genomic rearrangements has been so far reported. Methods: In order to identify predisposing variants, we analyzed—both by NGS and by comparative genomic hybridization/single-nucleotide polymorphism (CGH-SNP array) array—37 patients with a diagnosis of familial pulmonary fibrosis. Results: a total of 17 patients (46%) harbored copy number variations (CNVs), 10 (27%) did not harbor any CNVs, 5 (13.5%) showed a mosaic deletion of the Y chromosome, and 5 (13.5%) showed a run of homozygosity (ROH). NGS identified causative variants (including a novel one) in five patients (5/37, 13.5%) and confirmed the high prevalence of MUC5B promoter polymorphism rs35705950, including the detection of a previously unreported form in IPF SNP (indicated as “novel” in the main text), rs141420125 (23/37; 62%). Conclusions: CGH-SNP array identified CNVs containing genes involved in mechanisms (i.e., oxidative stress, mitophagy, NF-Kb pathway) that have been shown to play a role in the pathogenesis of IPF. Therefore, the application of CGH-SNP array or other quantitative tests should be considered in the diagnostic setup of these patients Full article

Ferritin heavy chain (FTH1) is a key subunit of ferritin and serves as a core regulator of iron metabolism, playing an important role in alleviating cellular damage caused by oxidative stress or regulating programmed cell death. This study identified 7 FTH1 homologs (AgFTH1-1 to AgFTH1-7) across the entire genome of Anadara granosa and investigated their expression responses during Vibrio infection. The 7 AgFTH1 genes are arranged in tandem across 6 chromosomes, with AgFTH1-5 and AgFTH1-6 undergoing gene amplification via a local duplication event. Among these homologous genes, 5 genes contain a single conserved ferritin domain (PF00210) and retain key ferroxidase center residues (Glu23, His65). Following Vibrio infection, these 5 genes exhibit downregulated expression, which may increase intracellular free iron and be consistent with ferroptosis-like cell death contributing to pathogen clearance, as suggested by previous studies. AgFTH1-5 contains a signal peptide and exhibits increased expression, suggesting it may regulate extracellular local iron storage. AgFTH1-4 (synaptonemal N-terminal SNARE) and AgFTH1-7 (GTPase domain) lack signal peptides, exhibit atypical structures, and show no significant expression changes under bacterial stress, indicating they may be associated with vesicle trafficking rather than classical iron storage. This study systematically analyzed the genomic features and expression patterns of the FTH1 gene family in A. granosa, laying a foundation for further revealing its role in shellfish immune defense. Full article

Xeroderma Pigmentosum group C (XP-C) is an autosomal recessive disorder caused by mutations in the XPC gene, leading to defective nucleotide excision repair. This defect leads to genomic instability and a profound cancer predisposition. To model this disease, we generated induced pluripotent stem cells (iPSCs) from an XP-C patient carrying a novel homozygous nonsense mutation in the XPC gene (c.1830C>A). The resulting iPSCs demonstrated typical pluripotent characteristics, including expression of key markers and trilineage differentiation capability. However, genomic assessment revealed progressive karyotypic instability during extended culture. While initial whole-genome sequencing detected no major chromosomal abnormalities, subsequent G-banding analysis identified acquired trisomy 12 in two lines (CL12 and CL27) and a derivative X chromosome in a third line (CL30). These abnormalities were absent in early-passage analyses, indicating that they were acquired and selected for during extended culture. The acquisition of a derivative X chromosome in CL30, alongside recurrent trisomy 12, represents a unique cytogenetic signature likely attributable to the underlying XPC defect. We hypothesize that the loss of GG-NER creates a permissive genomic environment, accelerating the accumulation of DNA damage and chromosomal missegregation under replicative stress. This temporal divergence in genomic integrity highlights how culture pressures drive chromosomal evolution in XP-C iPSCs independently of initial reprogramming. Our findings emphasize that XP-C iPSCs require continuous genomic surveillance and provide a model for investigating how DNA repair deficiencies interact with in vitro culture stress. Full article

Titanium dioxide (TiO₂), widely recognized as a whitening food additive, has been extensively employed in food products such as confectionery, sauces, and coffee creamers. The potential genotoxicity of TiO₂ has recently raised increasing concern, especially after the European Union prohibited its use as a food additive due to genotoxicity risks. The contradictory outcomes of in vitro and in vivo studies emphasize the necessity for more rigorous and systematic evaluation. In this study, we assessed the potential genotoxicity of food-grade TiO₂ in human intestinal cell lines and intestinal barrier models. Three distinct genotoxicity assays were conducted: the comet assay (DNA tail formation), chromosomal aberration analysis, and the micronucleus assay. The results revealed that TiO₂ exposure led to DNA damage primarily associated with oxidative stress in various intestinal cell systems at actual intake levels, regardless of metabolic activation; however, it did not trigger chromosomal aberrations or micronucleus formation. Thus, TiO₂ appears to cause in vitro genotoxic damage at the DNA level, but not at macroscopic endpoints, such as chromosomal aberrations or micronucleus formation. Further in-depth in vivo study is required to definitively determine the potential genotoxicity of TiO₂ in the food industry. Full article

Background/Objectives: Bauhinia cheilantha Bong. Steud. (Leguminosae; “pata-de-vaca”) is traditionally used in folk medicine for its antidiabetic, anti-inflammatory, and sedative properties. This study aimed to evaluate aqueous leaf extracts of B. cheilantha, non-delipidated and delipidated, regarding their phytochemical composition, phenolic profile, antioxidant potential, and cytotoxic, genotoxic, and antigenotoxic effects. Methods: Phytochemical screening was performed by TLC, and phenolic compounds were determined by HPLC. Antioxidant activity was assessed using DPPH, ABTS, and phosphomolybdenum assays. Cytotoxicity, genotoxicity, and antigenotoxicity were evaluated in L929 murine fibroblast cells using MTT and cytokinesis-block micronucleus (CBMN) assays. Results: Both extracts contained anthocyanins, phenolics, lignans, saponins, and hydrolyzable tannins. The delipidated extract showed higher total phenolic content (17.54 mg/kg) than the non-delipidated (13.76 mg/kg). Major constituents included kaempferol 3-glucoside, quercetin, hesperidin, naringenin, and t-cinnamic acid. Antioxidant assays revealed EC₅₀ values of 25.84, 13.60, and 66.09 µg/mL for the non-delipidated extract, and 26.19, 16.34, and 52.78 µg/mL for the delipidated extract in the DPPH, ABTS, and phosphomolybdenum assays, respectively. No cytotoxicity was observed, except at 1600 µg/mL for the non-delipidated extract and 800–1600 µg/mL for the delipidated extract. Genotoxicity occurred only at 400 µg/mL. Antigenotoxic evaluation showed that the non-delipidated extract (100 µg/mL) reduced methyl methanesulfonate-induced chromosomal damage in simultaneous and post-treatment conditions, while the delipidated extract was only effective for post-treatment. Conclusions: Aqueous extracts of B. cheilantha exhibit antioxidant and antigenotoxic properties. At active concentrations, they were non-cytotoxic and non-genotoxic. The non-delipidated extract, in particular, showed the strongest genome-protective potential, supporting its traditional use and highlighting its relevance in the development of natural therapeutic agents. Full article

Background/Objectives: Systemic sclerosis (SSc) is a rare, complex autoimmune disease characterized by fibrosis of the skin and internal organs. While its pathogenesis is not fully understood, chromosomal instability and telomere attrition have emerged as significant areas of investigation. Methods: This review provides a historical narrative perspective and synthesizes current findings on the role of these genomic anomalies in SSc pathogenesis. We synthesized findings from foundational and recent research articles investigating genotoxic factors, chromosomal aberrations, and telomere biology in SSc. Results: There is a strong historical basis for chromosomal instability in SSc, manifesting as micronuclei, translocations, and breaks. This instability is driven by clastogenic factors and oxidative stress. SSc-specific autoantibodies are implicated; anti-centromere antibodies correlate with aneuploidy and micronuclei, while anti-topoisomerase I may inhibit DNA repair. SSc is also characterized by significant telomere attrition, first reported in 1996 and now confirmed by additional genetic studies. This telomere loss is associated with reduced telomerase activity and the presence of autoantibodies against telomere-associated proteins, including shelterin components. Conclusions: We conclude that inflammation, telomere attrition, and chromosomal instability are linked in a self-perpetuating cycle that drives SSc pathogenesis. We propose that an initial inflammatory stimulus leads to reactive oxygen species production, causing telomere damage and attrition. Critically short telomeres trigger faulty DNA repair mechanisms, such as breakage–fusion–bridge cycles, resulting in chromosomal instability. This genomic damage, in turn, acts as a danger signal, further activating inflammatory pathways and creating a feedback loop that perpetuates fibrosis. Full article

Background and Clinical Significance: Tyrosine kinase inhibitors (TKIs) have transformed Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) into a largely manageable chronic disease. However, off-target toxicities are increasingly recognized; rarer complications such as bone marrow edema (BME) remain underreported. BME is a radiological syndrome characterized by excess intramedullary fluid on fat-suppressed T2/STIR magnetic resonance imaging sequences and may progress to irreversible osteochondral damage if unrecognized. We report a case series of TKI-associated BME and propose a practical diagnostic-therapeutic framework. Case Presentation: We describe three patients with Ph+ CML who developed acute, MRI-confirmed BME of the lower limb during TKI therapy. Case 1 developed unilateral then bilateral knee BME, temporally associated first with dasatinib and subsequently with imatinib; symptoms improved after TKI interruption, bisphosphonate therapy, and supportive measures, and did not recur after switching to bosutinib. Case 2 presented with proximal femoral BME during long-term imatinib; imatinib was stopped, intravenous neridronate administered, and bosutinib initiated with clinical recovery and later near-complete radiological resolution. Case 3 experienced multifocal foot and ankle BME during imatinib; symptoms resolved after drug discontinuation and bisphosphonate therapy, and disease control was re-established with bosutinib without recurrence of BME. All patients underwent molecular monitoring and mutational analysis to guide safe therapeutic switching. Discussion: Temporal association across cases and the differential kinase profiles of implicated drugs suggest PDGFR (and to a lesser extent, c-KIT) inhibition as a plausible mechanistic driver of TKI-associated BME. PDGFR-β blockade may impair pericyte-mediated microvascular integrity, increase interstitial fluid extravasation, and alter osteoblast/osteoclast coupling, promoting intramedullary edema. Management combining MRI confirmation, temporary TKI suspension, bone-directed therapy (bisphosphonates, vitamin D/calcium), symptomatic care, and, when required, therapeutic switching to a PDGFR-sparing agent (bosutinib) led to clinical recovery and preservation of leukemia control in our series. Conclusions: BME is an underrecognized, potentially disabling, TKI-related adverse event in CML. Prompt recognition with targeted MRI and a multidisciplinary, stepwise approach that includes temporary TKI adjustment, bone-directed therapy, and consideration of PDGFR-sparing alternatives can mitigate morbidity while maintaining disease control. Prospective studies are needed to define incidence, risk factors, optimal prevention, and management strategies. Full article

The growing production and use of silver nanoparticles continues to raise questions about their consequences for human and animal health. The method of production, particle stabilization, particle size, concentration, and duration of exposure to cells can affect their reactivity and, consequently, their toxicity. This study was conducted to determine the degree of harmfulness of colloidal silver compounds, including silver nanoparticles produced via the HVAD method, to mitotic chromosomes in chinchilla’s cells. Thanks to the sister chromatid exchange (SCE) test, chromosome damage during cell division, i.e., the actual toxic effect of the tested compounds, could be assessed. For this purpose, whole peripheral blood from chinchillas was exposed in vitro to three colloidal silver compounds (unstable AgNP-HVAD, sodium citrate-stabilized silver nanoparticles—[AgNP+C], and silver nitrate) for 3, 6, and 24 h. The toxicity of these compounds was assessed at concentrations of 5, 10, and 20 µg/L and the occurrence of sister chromatid exchanges on chromosomes, resulting from double-strand DNA breaks, was analyzed. The studies revealed a notable increase in SCEs compared to the control group, suggesting the genotoxic properties of the examined AgNPs. The highest level of chromosome damage was observed following exposure to citrate-stabilized silver nanoparticles. Further research is needed to better understand the toxicological mechanisms of AgNPs produced via the HVAD method and their effects on mammalian somatic cells. Full article

Homology search is a means through which DNA double-strand breaks (DSBs) explore the genome for sequences that enable error-free repair, known as homologous recombination. A better understanding of this search process is fundamental to the relationship between higher-order chromosome organization and DNA damage. Here, we use an entropic bead-spring polymer chain model to simulate the spatiotemporal dynamics of the yeast genome during interphase. The chromosome is organized by transient and dynamic cross-links representing structural maintenance of chromosome (SMC) complexes. DNA damage is modeled as a break in the bead-spring chain, coupled with a removal of crosslinks from beads proximal to the break site. We show that the removal of cross-links drives the exploration of genomic space by the damaged ends, while rates and densities of intact dynamic crosslinking have only a minor role. Local depletion of SMC cross-links proximal to the break site enables the damaged segment to escape the chromosome territory and enhances its ability to explore the genome. Our study reveals a foundational principle by which DSBs can encounter distant regions of sequence homology. Full article

While PARP inhibitors like Olaparib are effective against BRCA1-deficient breast cancers, their efficacy in BRCA1-proficient tumors depends on the functional status of homologous recombination (HR) repair. Here, we identify the structure-specific endonuclease SLX1 as a key regulator of HR and a determinant of Olaparib sensitivity in BRCA1-intact breast cancer. SLX1 is frequently upregulated in breast cancer and associated with poor prognosis. Functional studies revealed that SLX1 promotes RAD51-mediated HR repair of DNA double-strand breaks. Consequently, SLX1 depletion reduces HR efficiency, increases chromosomal instability, and sensitizes breast-proficient breast cancer cells to DNA-damaging agents, including camptothecin, ionizing radiation, and Olaparib. In contrast, SLX1 overexpression enhances DNA repair capacity and promotes Olaparib resistance. In vivo, SLX1 knockdown synergizes with Olaparib to suppress tumor growth in xenograft models. These findings establish SLX1 as a critical regulator of HR function in BRCA1-proficient breast cancer and a promising target for restoring PARP inhibitor sensitivity through induced HR deficiency. Full article

High-grade serous ovarian cancer (HGSOC) is the most common (~80%) and lethal ovarian cancer subtype in the United States, characterized by TP53 mutations and DNA repair defects causing chromosomal instability (CIN). KIF18A is an essential cytoskeletal motor protein for cell division in CIN+ cancer cells, but it is not necessary for cell division in normal cells. Therefore, KIF18A represents a promising target for therapeutic interventions in CIN+ cancers. We investigated the use of a novel KIF18A inhibitor ATX020, for selectively targeting CIN+ HGSOC cells using growth inhibition assays, invasion assays, immunoassays, cell cycle analysis, and immunofluorescence techniques. Using DepMap and flow cytometry, we classified a panel of HGSOC cell lines based on aneuploidy scores (AS) and ploidy levels and identified a correlation between these classifications and sensitivity against ATX020. ATX020 induced cytotoxicity through mitotic arrest and DNA damage, and reduced tumor growth in HGSOC with high aneuploidy scores (AS). Mechanistically, ATX020 blocks KIF18A’s plus-end movement on spindle fibers, increasing spindle length, resulting in chromosomal mis-segregation, aneuploidy, and DNA damage. Our findings suggest that ATX020 inhibits CIN+ HGSOC cells mainly by inducing mitotic arrest and DNA damage, disrupting KIF18A’s function crucial for mitosis. Full article

The Paraoxonase (PON) gene family consists of three paralogues (PON1, PON2 and PON3) that are tandemly located on chromosome 7. In this review paper, the structure and function of the encoded proteins is summarized. In addition, an overview is given on the generated animal models. Finally, their involvement in the pathogenesis of different diseases is discussed, starting from an extended screening of the literature using PUBMED and Web of Science. PON1 and PON3 are mainly expressed in the liver and released into the bloodstream, bound to high-density lipoprotein. PON2 is expressed in various tissues, including the liver, lungs, heart, placenta and testes, but remains intracellular. The name of the enzyme family reflects PON1′s ability to neutralize paraoxon, but they also exhibit lactonase and esterase activities. All three PON enzymes play a role in reducing lipid peroxides in High-Density Lipoproteïne (HDL) and low-density lipoprotein(LDL), giving them antioxidant properties. This links them to Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD), a metabolic liver condition marked by the excessive accumulation of triglycerides (TG) in liver cells. In addition to their association with MASLD, the PON genes are, due to their antioxidant properties, also associated with other conditions including cardiovascular diseases, chronic kidney disease, neurological and immunological conditions up to some forms of cancer. In the latter, the antioxidant properties can result in tumor progression by protecting malignant cells from oxidative damage thus supporting survival, proliferation and metastasis indicating them as potential drug targets for treatment of cancer. Therefore, further research on this protein family can provide novel insights into their function and their potential therapeutic applicability. Full article

Extrachromosomal circular DNA (eccDNA) has been recognized as a key player in tumorigenesis and progression. However, eccDNA transcriptional regulatory mechanisms under DNA damage in cancer remain poorly characterized. Here, we used doxorubicin to induce DNA damage in the hepatocellular carcinoma cell line HepG2 and performed Circle-seq to profile eccDNAs before and after the damage. We observed a significant increase in the number, length, and chromosomal distribution density of eccDNAs following DNA damage. RNA-seq revealed that the expression of genes carried on eccDNA was positively correlated with eccDNA copy number under DNA damage. Further ATAC-seq profiling identified distinct chromatin characteristics at eccDNA breakpoint regions compared to other regions of eccDNA and linear genomic regions. Additionally, eccDNAs generated under DNA damage preferentially originated from linear genomic regions characterized by low GC content and hypomethylation. Finally, by integrating Hi-C and H3K27ac ChIP-seq, we uncovered that eccDNAs with mobile enhancer activity (ME-eccDNAs) display significantly enhanced chromatin interactions and H3K27ac enrichment after DNA damage. Overall, our findings systematically elucidate the DNA damage-driven mechanisms underlying eccDNA biogenesis, chromatin characteristics and transcriptional regulation in HCC HepG2 cells. Full article

There is increasing research interest in the ORF3 accessory protein of PEDV as a critical element for viral virulence. Here, wild type ORF3 (ORF3_wt) gene was constructed in pEGFP-C1 vector. Additionally, two truncation mutants, ORF3-N (1-98 amino acids [aa]) and ORF3-C (99-224 aa) were inserted in the same vector. Results of ORF3 expression revealed early cytoplasmic localization but 12 h after transfection, ORF3 accumulated around the nucleus, especially ORF3-N. This caused chromosome condensation and morphological distortion that culminated in cell death. In comparison with the native cells expressing GFP alone, ORF3wt-induced lethality was 6.61% above baseline while ORF3- C expression resulted in moderate increase in cell death (0.64%). ORF3-N was affected the most with 220.32% increased lethality. It was, therefore, inferred that the ORF3 gene encodes a protein that causes nuclear damage, distorts cell morphology and leads to cell death. Furthermore, the role of the protein could be inherent in the N-terminal domain, which consists of the transmembrane domains. These findings underpin the importance of ORF3 gene expression in the host and are rudimental insights for further exploration into the mechanistic interactions of ORF3 and the host, as well as a possible role in pathogenesis in PEDV and other coronaviruses. Full article

Despite the recognized social and economic importance of common beans (Phaseolus vulgaris L.), the average grain yield is far below the productive potential of cultivars. This situation is explained by several factors, such as the large number of diseases and pests that affect the crop, some of which cause significant damage. It is estimated that approximately 200 diseases can significantly affect common beans. These can be bacterial, viral, fungal, and nematode-induced. The main bean fungal diseases include anthracnose, angular leaf spot, powdery mildew, gray mold, Fusarium wilt, dry root rot, Pythium root rot, southern blight, white mold, charcoal rot and rust. This review provides a comprehensive overview of eleven major fungal diseases affecting common bean, describing their associated damage, characteristic symptomatology, and the epidemiological factors that favor disease development. It further synthesizes current knowledge on host resistance mechanisms that can be exploited to develop molecularly informed resistant genotypes. The compilation includes characterized resistance genes and mapped quantitative trait loci (QTLs), with details on their chromosomal locations, genetic effects, and potential for use in breeding. Moreover, the review highlights successful applications of molecular breeding approaches targeting fungal resistance. Finally, it discusses conclusions and future perspectives for integrating advanced genetic improvement strategies—such as marker-assisted selection, genomic selection, gene editing, and pyramiding—to enhance durable resistance to fungal pathogens in common bean. This work serves as both a reference for forthcoming resistance-mapping studies and a guide for the strategic selection of resistance loci in breeding programs aimed at developing cultivars with stable and long-lasting fungal resistance. Full article