Search Results (120)

Acute myeloid leukaemia (AML) remains a highly lethal malignancy with poor prognosis in adults above 60 years old and often occurs after radiation exposure. Emerging evidence suggests that circadian rhythm disruption, prevalent in shift workers, may contribute to cancer development. Clock genes (CGs) regulate fundamental cellular processes, including the DNA damage response (DDR), cell cycle progression, and haematopoiesis. In the absence of substantial experimental data, this review examines the potential pathways linking circadian clock dysregulation to radiation-induced AML (rAML) and evaluates how temporal disruption may modulate leukaemogenesis and radiation-induced effects. The evidence was synthesised on core clock components (BMAL1, CLOCK, PER, CRY, REV-ERB, ROR), their dysregulation in AML, and their roles in radiation response. Epigenetic and post-transcriptional regulatory mechanisms, including m⁶A RNA modification and sirtuin-mediated chromatin remodelling, were evaluated for their contribution to circadian-regulated DNA repair capacity. Multiple CGs demonstrated aberrant expression in AML, with BMAL1 showing tissue-specific dysregulation, and PER1/2/3 was consistently downregulated in peripheral blood. Clock proteins directly regulate DNA damage checkpoints through interactions with ATM/CHK2 and p53 pathways. Circadian disruption enhances inflammatory signalling, promotes accumulation of myeloid-derived suppressor cells, and accelerates immune senescence. Moreover, radiation exposure modulates CG expression, which may alter repair fidelity and increase leukaemogenic risk. Understanding these connections in the context of disrupted circadian rhythms could help identify at-risk populations and improve shift workplace health policies. Full article

Ataxia-Telangiectasia (A-T) is a multisystem disorder caused by loss of A-T mutated (ATM) protein activity, characterized clinically by immunodeficiency and cerebellar ataxia. ATM is a master regulator of DNA damage responses and loss of ATM function is accompanied by persistent activation of PARP1 leading to depletion of intracellular NAD⁺ and dysfunction of a series of cellular signalling pathways dependent on NAD⁺, providing a mechanistic rationale for NAD⁺ augmentation therapy. We performed a clinical trial of NAD⁺ augmentation with nicotinamide riboside (NR) over 24 months in A-T patients where we observed improved coordination and eye movements in A-T patients. Here, by using peripheral blood mononuclear cells, we performed longitudinal transcriptome profiling to define molecular signatures of A-T and to assess pathway-level responses to NR supplementation. A-T patients exhibited reproducible transcriptomic alterations involving immune, vascular, and inflammatory pathways. NAD⁺ augmentation was associated with suppression of interferon response genes and modulation of networks correlated with neurological improvement. These findings establish systemic molecular signatures of A-T and identify potential blood-based biomarkers that reflect disease processes and therapeutic response, supporting the use of NAD⁺ augmentation as a disease-modifying strategy in A-T by dampening interferon signalling. Full article

An undescribed seco-kaurane diterpenoid, benincaside A (BA), was isolated from the seeds of Benincasa hispida. The seeds of B. hispida have been traditionally used in folk medicine and previous studies have reported anti-tumor potential in B. hispida seed extracts. Accordingly, we investigated the cytotoxicity and underlying mechanisms of BA in colorectal cancer cells. BA inhibited growth in HT29, Colo205, HCT116, and CT26 colorectal cancer cells, as determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, while showing no toxicity toward normal human umbilical vein endothelial cells (HUVEC) and human fibroblast WS-1 cells. In HCT116 cells, BA-induced deoxyribonucleic acid (DNA) damage and apoptosis, as evidenced by morphological changes, 4,6-diamidino-2-phenylindole dihydrochloride (DAPI) staining, and assays of caspase-8 and caspase-3 activities. BA triggered apoptotic cell death via the extrinsic pathway, as indicated by elevated caspase-8 and caspase-3 activities. Intracellular reactive oxygen species (ROS) generation was observed in BA-treated HCT116 cells. The growth-inhibitory effects were significantly attenuated by pretreatment with N-acetylcysteine (NAC, an antioxidant), caffeine (an ATM kinase inhibitor), z-VAD-fmk (pan-caspase inhibitor), or z-IETD-fmk (caspase-8-specific inhibitor). Colorimetric assays confirmed increased caspase-8 and caspase-3 activities in BA-treated cells. This study is the first to report ROS-dependent signaling as a key mechanism underlying BA-induced cell death in HCT116 human colorectal cancer cells. Full article

Background/Objectives: Pancreatic ductal adenocarcinomas (PDACs) are lethal tumors exhibiting resistance to most cancer therapeutics, particularly DNA-damaging agents. The KRAS oncogene drives PDACs, and many of these tumors are addicted to it and its downstream effectors. One such effector is Rac1, a small GTPase involved in actin cytoskeleton remodeling and regulation of the DNA damage response. We previously showed that Rac1 inhibition blocks activation of ATM/Chk2 and ATR/Chk1 pathways in response to gamma rays, sensitizing PDAC cells to radiation. Methods: Western blot analyses were used to assess the impacts of Rac1 inhibition on the components of the ATR/Chk1 cascade. Results: Here, we show that Rac1 inhibition disrupts ATR/Chk1 signaling by promoting degradation of Claspin, a key component of the fork protection complex needed for the Ser345-phosphorylation of Chk1 by ATR. In PDACs and normal pancreatic ductal cells, Rac1 inhibition (via inhibitors or siRNA) decreased Claspin protein levels without affecting its mRNA, reflecting a >3-fold reduction in Claspin’s half-life. Claspin contains a phosphodegron recognized by SCF^βTrCP E3 ubiquitin ligase when phosphorylated at Ser30/Ser34, a process involving PLK1 kinase. In PDAC cells, Claspin degradation upon Rac1 inhibition required the proteasome and βTrCP1/2 proteins, and was blocked by the mutagenesis of Ser30/Ser34, but occurred independently of PLK1 activity. Although Rac1 inhibitors reduced Claspin in both normal and cancer cells, PDAC cells may be uniquely vulnerable due to elevated replication stress and greater reliance on ATR/Chk1. Accordingly, Claspin depletion sensitized PDAC cells but not normal cells to gamma rays, inducing apoptosis only in cancer cells. Conclusions: These findings identify Rac1 as a critical regulator of ATR/Chk1 signaling through stabilization of the fork protection protein Claspin. Rac1 inhibition promotes the βTrCP-dependent, proteasome-mediated degradation of Claspin via its phosphodegron, thereby impairing Chk1 activation in response to DNA damage. Full article

Chronic inhalation exposure to nanoplastics, specifically polyethylene terephthalate (PET) nanoplastics (PET-NPLs) is an emerging health concern, yet the long-term consequences for genomic stability and DNA damage response (DDR) capacity in bronchial epithelial cells remain poorly characterized. For this study, human bronchial epithelial BEAS-2B cells were continuously exposed to PET-NPLs for over 20 weeks, after which elevated basal DNA genotoxic damage was observed, as assessed by the alkaline comet assay. In addition, a broad transcriptional suppression of the DDR, with 27 of 84 profiled genes involved in DDR showing reduced expression relative to passage-matched control was observed. The suppressed genes span ATM/ATR checkpoint signaling, homologous recombination (HR), base excision repair (BER), nucleotide excision repair (NER), and apoptotic pathways. To determine whether chronic PET-NPL exposure altered susceptibility to acute genotoxic challenge in a damage-type-specific manner, cells were treated with methyl methanesulfonate (MMS), ultraviolet-C (UV-C) radiation, or bleomycin. While MMS and UV-C induced comparable levels of DNA damage in control and PET-exposed cells, bleomycin produced significantly greater damage in PET-exposed cells, indicating selective sensitization to doble-strand breaks (DSB)-type and oxidative genotoxic insults. Transcriptional profiling during bleomycin challenge identified 18 DDR genes with relatively higher expression in PET-exposed cells compared to passage-matched controls, encompassing HR, BER, ATM/ATR signaling, the Fanconi anemia pathway, and apoptosis. Furthermore, PET-exposed cells retained significantly higher residual DNA damage after 3 h of bleomycin challenge, indicating a persistent early repair deficit. Together, these findings suggest that chronic PET-NPL exposure specifically compromises the bronchial epithelial DDR, with potential implications for long-term genomic stability in respiratory epithelia subjected to nanoplastic inhalation. Full article

Cervical cancer constitutes a major global health burden with a high incidence rate. Despite its well-established role in genome stability and cell cycle regulation, its specific anti-tumor mechanism involving the induction of a senescence-like state remains unclear. To determine whether Mg²⁺ impedes cervical cancer progression through the induction of a senescence-like phenotype via the ATM/CHK2/p21 pathway, HeLa cells were used in this study. Cell proliferation, migration, and invasion were measured using CCK-8, EdU, wound-healing, and Transwell assays, while SA-β-gal staining and western blotting served to examine both senescence-related markers and pathway protein expression. A BALB/c nude mouse xenograft model was established to evaluate tumor growth and safety following intratumoral Mg²⁺ injection. The results showed that Mg²⁺ inhibited proliferation, migration, and invasion in a concentration-dependent manner. Treatment with 20 mM Mg²⁺ increased SA-β-gal positivity, decreased Lamin B1 expression, and activated the ATM/CHK2/p21 pathway; moreover, this upregulation of p21 was reversed by an ATM inhibitor. ELISA revealed that 10 mM Mg²⁺ enhanced IL-6 and TNF-α secretion, confirming effective induction of the senescence-associated secretory phenotype, while higher concentrations diminished this effect, which may be partly attributed to the reduction in cell viability. In vivo experiments showed that Mg²⁺ inhibited tumor growth without notable alterations in body weight, liver and kidney function, or serum magnesium levels. In summary, the localized high concentration of magnesium ions induces cells to enter a senescence-like state via the ATM/CHK2/p21 pathway, thereby selectively suppressing malignant cellular behaviors. Notably, its in vivo efficacy and safety profile in vivo are favorable. It is also worth noting that these findings should be interpreted within the context of a preclinical, high-dose local Mg²⁺ model. Full article

Chronic exposure to benzo[a]pyrene (BaP), a Group 1 IARC carcinogen, is a major driver of lung carcinogenesis; however, how sustained subcytotoxic exposure reprograms bronchial epithelium toward preneoplastic states remains poorly defined. Here, we subjected BEAS-2B human bronchial epithelial cells to 12 weeks of continuous BaP at environmentally relevant concentrations (0.1 and 1.0 µM) and interrogated the resulting phenotypes using an integrated multi-scale framework encompassing functional toxicology, RT-qPCR, RNA-seq, phospho-kinase/NF-κB arrays, and organotypic air–liquid interface (ALI) cultures. Cells maintained metabolic competence throughout, evidenced by sustained CYP1A1 and CYP1B1 induction at both acute (4 h) and chronic (12-week) timepoints, while accumulating genotoxic stress as demonstrated by dose-dependent nuclear γ-H2AX foci formation and ATM phosphorylation (Ser1981). RNA-seq revealed a dose-dependent transcriptional shift: 0.1 µM BaP yielded 119 differentially expressed genes (DEGs; |log2FC| ≥ 1, FDR < 0.05), whereas 1.0 µM generated 255 DEGs. Downregulated transcripts were enriched for extracellular matrix and cell-adhesion programs (COL14A1, ADAMTS2, CSMD3, CADM3), while upregulated genes encompassed inflammatory, calcium-signaling, and vesicle-trafficking modules (NFATC4, CSF2RA, SYT1, PCLO). Phospho-kinase/NF-κB arrays confirmed a p53/NF-κB signaling nexus, with concurrent activation of MAPK/ERK (Thr202/Tyr204) and PI3K/Akt (Ser473) pathways. Despite persistent genotoxic stress, cells did not acquire anchorage-independent growth and remained non-tumorigenic in vivo. Critically, ALI organotypic cultures derived from BaP-exposed cells exhibited histological dysplasia, nuclear pleomorphism, and disrupted apical-basal polarity. These findings mechanistically link chronic BaP exposure to an initiation-like preneoplastic state and establish a validated 2D/3D multi-omics platform for PAH-driven lung carcinogenesis research. Full article

Colorectal cancer (CRC) remains a significant global health burden, with growing evidence highlighting microbial contributions to its pathogenesis. Certain genotoxigenic bacteria, such as Escherichia coli, Campylobacter jejuni, and Helicobacter pylori, produce virulence factors that induce DNA damage, genomic instability, and chronic inflammation—key features of carcinogenesis. At the same time, viruses such as JC polyomavirus (JCPyV), considered potentially oncogenic, and established oncogenic viruses like Epstein–Barr virus (EBV) and human papillomavirus (HPV) have been detected in colorectal tissues and are linked to cell cycle regulation, apoptosis, and DNA repair through their viral proteins. Intriguingly, recent findings suggest that bacterial genotoxins may promote the reactivation or transcriptional activity of persistent viruses such as JCPyV and EBV, possibly through DNA damage-induced stress and activation of NF-κB- or ATM-dependent signaling pathways. Despite these advances, interactions between oncogenic viruses and bacteria within the colon microbiome remain underexplored. This review integrates current evidence and provides future perspectives for addressing potential genotoxic collaboration between bacteria and viruses that could contribute to colorectal tumorigenesis. Elucidating these interactions could reveal novel biomarkers and therapeutic targets for the prevention and treatment of CRC. Full article

Aortic diseases, including thoracic and abdominal aneurysms as well as aortic dissections, represent life-threatening vascular disorders characterized by progressive wall degeneration and inflammation. Increasing evidence indicates that oxidative stress is a central driver of aortic pathology through the induction of DNA damage in vascular smooth muscle cells and endothelial cells. Oxidative DNA lesions activate the DNA damage response (DDR), a highly coordinated network of damage sensors, signaling kinases, and repair effectors that determines cell fate decisions such as DNA repair, apoptosis, or cellular senescence. In aortic tissue, persistent or dysregulated DDR signaling contributes to chronic inflammation, extracellular matrix degradation, and loss of vascular integrity. Key molecular regulators, including base excision repair enzymes OGG1 and APE1, as well as DDR mediators such as ATM, ATR, p53, PARP, and NOTCH1, integrate oxidative stress signals with pro-inflammatory and pro-degenerative pathways. Aberrant activation of these mechanisms promotes vascular smooth muscle cell VSMC phenotypic switching from contractile to synthetic phenotype, endothelial dysfunction, and senescence-associated secretory responses, thereby accelerating aortic wall weakening and aneurysm progression. This review highlights the mechanistic links between oxidative stress-induced DNA damage, DDR pathway activation, and vascular remodeling in aortopathies. A deeper understanding of these molecular interactions may uncover novel biomarkers and therapeutic targets aimed at limiting inflammation, preserving genomic stability, and preventing catastrophic aortic events. This work represents a narrative review and therefore has inherent limitations in terms of systematic literature search and selection. Full article

The incidence of early-onset colorectal cancer (EOCRC; <50 years) continues to increase, with the most rapid rises occurring among Hispanic/Latino (H/L) populations who remain underrepresented in molecular research. Because the TP53 signaling pathway is a key driver of colorectal tumorigenesis, this study aimed to clarify its prognostic significance in FOLFOX-treated EOCRC across ancestry groups. We analyzed 2515 colorectal cancer (CRC) cases (266 H/L, 2249 non-Hispanic White [NHW]) stratified by ancestry, age at onset, and FOLFOX exposure. Fisher’s exact, chi-square, and Kaplan–Meier’s analyses were applied, and multi-dimensional data integration was performed using AI-HOPE and AI-HOPE-TP53, conversational artificial intelligence platforms enabling natural language-driven exploration of clinical, genomic, and therapeutic features. TP53 pathway alterations were common in both H/L (85%) and NHW (83%) FOLFOX-treated patients. Among late-onset NHW cases, FOLFOX treatment was associated with higher TP53 mutation frequencies and lower ATM and CDKN2A mutation rates compared with untreated counterparts, while CHEK2 alterations were significantly less frequent in late-onset H/L patients. Missense mutations were the predominant alteration type across groups. These findings suggest that TP53 pathway alterations may be associated with ancestry- and treatment-specific clinical patterns in EOCRC and illustrate how AI-enabled integrative analytic frameworks can facilitate hypothesis generation and prioritize candidate biomarkers for future validation in precision oncology. Full article

Background: Radiation therapy is an important treatment method for non-small-cell lung cancer (NSCLC). However, predicting patient prognosis remains challenging due to considerable interpatient heterogeneity. The TP53 signaling pathway, implicated in tumor radiosensitivity and treatment outcomes, represents a promising predictive biomarker. Accordingly, in this study, we aimed to identify TP53-signaling pathway-related genes and develop a novel prognostic model for risk stratification for NSCLC patients undergoing radiation therapy. Methods: Publicly available NSCLC transcriptomic datasets were obtained from the GEO and TCGA databases. Utilizing bioinformatics approaches, we identified differentially expressed genes (DEGs) associated with the TP53 signaling pathway. Feature selection was performed using LASSO regression, followed by the construction of a multivariate-Cox-regression-based prognostic prediction model. In vitro validation was performed using a cell viability assay, colony formation, cell cycle analysis, apoptosis detection, γH2AX immunofluorescence staining and comet electrophoresis. In vivo validation was performed utilizing a subcutaneous tumor-bearing mouse model, where radiosensitivity was assessed by monitoring tumor volume post-irradiation. Results: We constructed a robust prognostic prediction model based on five TP53-signaling-pathway-related genes (MDM2, THBS1, TP53I3, ATM, and SESN3), achieving a 5-year AUC of 0.828 in the training set and a 3-year AUC of 0.824 in the validation set. The model exhibited a significant ability to stratify patients into distinct high- and low-risk groups, demonstrating good predictive performance. The poor prognosis observed in the high-risk group was associated with lower infiltration of anti-tumor immune cells but higher infiltration of immunosuppressive cells. Both in vitro and in vivo experiments demonstrated that TP53I3 knockdown significantly enhanced the radiosensitivity of NSCLC through increased DNA damage, cell cycle arrest and apoptosis. Conclusions: In this study, a five-gene signature derived from the TP53 signaling pathway was developed, and the model was shown to effectively predict the prognoses of NSCLC patients undergoing radiotherapy. This signature has the potential to be developed into a clinically applicable tool for personalizing radiotherapy regimens for NSCLC. Full article

Bakuchiol (BAK), a natural meroterpenoid with antioxidant, anti-inflammatory and anticancer properties, has recently gained attention as a potential adjunct in breast cancer therapy. This review contextualizes breast cancer as a major global health challenge and highlights BAK as a bioactive compound capable of modulating pathways relevant to tumor development and progression. A structured literature search identified studies examining its molecular activity, pharmacological profile, and effects on breast cancer cells and stem cells. Results show that BAK influences oxidative stress regulation, mitochondrial function, apoptosis and estrogen receptor signaling while also affecting PI3K/AKT, MAPK, NF-κB, and EMT-related pathways. In breast cancer models, BAK acts as a selective phytoestrogen, induces S-phase arrest, activates the ATM/ATR–Chk1/Chk2 axis, and triggers mitochondrial apoptosis, particularly in ERα-positive cells. It also suppresses breast cancer stem-cell renewal, promotes BNIP3- and DAPK2-mediated apoptosis, reduces metabolic and transcriptional drivers of metastasis, and shows enhanced anticancer activity in derivative forms. These findings suggest that BAK may provide therapeutic benefit across several mechanisms central to breast cancer biology. In this review, the inclusion criteria encompassed publications describing the action of bakuchiol, its chemical and pharmacological properties, as well as its role in the treatment of various conditions, including cancers. Exclusion criteria included works not related to BAK or its therapeutic use in breast cancer, as well as publications that did not meet basic scientific standards, such as lacking methodological rigor or presenting a low level of scientific evidence. However, current evidence is predominantly in vitro, and limitations such as poor bioavailability and lack of clinical validation underscore the need for further in vivo and translational studies before therapeutic application can be established. Full article

Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy, often diagnosed at advanced stages with poor survival outcomes. Homologous recombination (HR), a major DNA double-strand break (DSB) repair pathway, safeguards genomic stability via error-free repair. While HR deficiency has been well established as a driver of genomic instability and tumorigenesis in several cancer types, the role of HR in HNSCC remains relatively understudied. Methods: Here, we analyzed the expression patterns of key HR proteins in HNSCC and investigated their association with clinical parameters, DNA methylation, immune cell infiltration, and patient survival outcome. Results: Surprisingly, our results demonstrate that HR factors are consistently upregulated in HNSCC, in both HPV-positive and HPV-negative groups. Survival analysis identified many HR factors, including ATM, BRCA1, BRCA2, PALB2, LIG1, RPA1, and RPA2, as potential prognostic biomarkers for better overall survival. Interestingly, we observed a significant correlation between HR protein overexpression and immune cell infiltration in HNSCC, suggesting a potential immunomodulatory role of HR proteins. To experimentally validate this association in both HPV-positive and -negative cell lines, we showed that MRE11 and RAD51 overexpression in HNSCC cells led to increased phosphorylation of IRF3 and STAT1, indicating activation of the cGAS/STING-mediated innate immune signaling. Conclusion: Together, our findings provide a comprehensive overview of the HR pathway in HNSCC, highlighting the dual role of HR proteins in both genomic maintenance and immune regulation. The consistent upregulation of HR proteins, their association with disease progression, and potential immunogenic effects underscore their promise as diagnostic/prognostic biomarkers and therapeutic targets in HNSCC. Full article

Plastic pollution is a growing environmental and health issue due to the increasing presence of micro- and nanoplastics in terrestrial and aquatic ecosystems. Polystyrene nanoplastics (PS-NPs) are among the most extensively studied because of their wide occurrence, physicochemical stability, and availability for laboratory research. Their nanoscale size enables interaction with biological systems at the molecular level, promoting internalization, intracellular trafficking, and potential bioaccumulation. This review summarizes current knowledge on the cellular effects and molecular mechanisms of PS-NPs, particularly in human gastrointestinal models. The gastrointestinal tract is a primary route of nanoplastic exposure, where PS-NPs can cross epithelial barriers, interact with immune and epithelial cells, and disturb cellular homeostasis. Once internalized, PS-NPs can induce oxidative stress, mitochondrial dysfunction, and dysregulation of autophagy, leading to alterations in lipid and glucose metabolism. Excessive synthesis of reactive oxygen species may trigger DNA damage, activate the ATM/ATR–p53 signaling pathway, and impair DNA repair mechanisms, thereby contributing to genomic instability. Emerging evidence also shows that PS-NPs can interact with ion channels, affecting calcium homeostasis, membrane potential, and cell viability. Overall, these findings highlight the complex and multifaceted toxicity of PS-NPs at the cellular level and underscore the need for further research to assess the long-term risks of nanoplastic exposure. Full article

Background: Glioblastoma (GBM) remains refractory to chemoradiotherapy. Glial populations—microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage—shape both treatment resistance and radiation-related brain injury. Scope: We synthesize how myeloid ontogeny and plasticity, astrocytic hubs (IL-6/STAT3, TGF-β, connexin-43/gap junctions), and oligodendrocyte precursor cells (OPCs)–linked programs intersect with DNA-damage responses, hypoxia-driven metabolism, and extracellular vesicle signaling to support tumor fitness while predisposing normal brain to radiotoxicity. Translational implications: Convergent, targetable pathways (IL-6/JAK–STAT3, TGF-β, chemokine trafficking, DDR/senescence) enable co-design of radiosensitization and neuroprotection. Pragmatic levers include myeloid reprogramming (CSF-1R, CCR2), astrocyte-axis modulation (STAT3, TGF-β, Cx43), and brain-penetrant DDR inhibition (e.g., ATM inhibitors), paired with delivery strategies that raise intratumoral exposure while sparing healthy tissue (focused-ultrasound blood–brain barrier opening, myeloid-targeted dendrimers; Tumor Treating Fields as an approved adjunct therapy). Biomarker frameworks (TSPO-PET, macrophage-oriented MRI radiomics, extracellular vesicle liquid biopsy) can support selection and pharmacodynamic readouts alongside neurocognitive endpoints. Outlook: Timing-aware combinations around radiotherapy and hippocampal/white-matter sparing offer a near-term roadmap for “glia-informed” precision radiotherapy. Full article