Therapeutic potential of 1,3,4-oxadiazole derivative in EAE-induced optic neuritis.

SFPQ Promotes Homologous Recombination via mRNA Stabilization of RAD51 and Its Paralogs.

The impact of chemical structure on redox behavior and biological activity of hydroxybenzoic acids.

This study aimed to investigate the function of KLF11 in regulating radiosensitivity (RT) in esophageal squamous cell carcinoma (ESCC) and to elucidate the underlying mechanisms. A nude mouse ESCC xenograft model was established by injecting KYSE150 cells into the left dorsal flank. Cell proliferation was assessed using cell counting kit-8 (CCK-8) and colony formation assays, while DNA damage was evaluated via a neutral comet assay. Key gene and protein expression levels were analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, and immunohistochemistry. Additionally, coimmunoprecipitation and immunofluorescence were employed to validate proteinprotein interactions. KLF11 expression was upregulated in both ESCC and RT-resistant tissues. At the cellular level, KLF11 expression was higher in ESCC cell lines than in the normal esophageal epithelial cell line HET-1A, with the most pronounced upregulation in KYSE150 cells and the least in TE1 cells. Notably, KLF11 knockdown under ionizing radiation exposure suppressed proliferation and colony formation, promoted apoptosis, and increased the expression of the DNA damage marker γ-H2AX as well as overall DNA damage levels in KYSE150 cells. Conversely, KLF11 overexpression in TE1 cells led to the opposite phenotype, suggesting that KLF11 confers RT resistance in ESCC by mitigating DNA damage. Further investigations revealed that KLF11 primarily repairs RT-induced DNA damage through the homologous recombination (HR) pathway rather than through nonhomologous end joining (NHEJ). Additionally, the expression of MDM2, E2F1, and RAD51 was significantly elevated in ESCC and RT-resistant ESCC tissues. Mechanistically, KLF11 promotes MDM2 expression, which inhibits E2F1 ubiquitination, thereby stabilizing E2F1 protein levels and enhancing RAD51-mediated HR repair, ultimately leading to RT resistance in ESCC. This study elucidates the critical role and molecular mechanism through which KLF11 drives radiotherapy resistance in ESCC by regulating the MDM2/E2F1 axis and enhancing HR repair, thereby providing a solid theoretical foundation and potential target for the development of KLF11-targeted radiosensitization therapies for ESCC.

Dynamic regulation of K33- and K48-linked ubiquitination of Tip60 by TRIM37 orchestrates host DNA damage response during Pseudomonas aeruginosa infection and recovery.

Freeze-thaw injury is a major cause of winter mortality in woody plants; however, the molecular mechanisms linking freeze-thaw stress to DNA damage and repair remain poorly defined. Here, we investigated the physiological thresholds of freeze-thaw injury in poplar and identified key regulatory components that enhance cold tolerance through improved DNA damage repair. Field temperature monitoring and differential scanning calorimetry revealed an effective freeze-thaw threshold of approximately 12°C, beyond which cumulative intracellular damage occurs despite the absence of extreme low temperatures. Integrated lncRNA, miRNA and mRNA sequencing demonstrated coordinated regulation of a DNA replication gene, PySLD5, by two long non-coding RNAs (MSTRG.19225.8 and MSTRG.19233.11) and the microRNA ptc-miR6476a. Functional assays, including pull-down, dual-luciferase and structural modelling, validated direct interactions among these RNAs and PySLD5. Overexpression of PySLD5 conferred enhanced cold tolerance, reduced electrolyte leakage and lower DNA fragmentation after freeze-thaw stress, whereas knockout lines showed severe cold sensitivity, disease susceptibility and reduced survival. Comet assays confirmed that repeated freeze-thaw cycles caused cumulative DNA damage. Together, these findings support a DNA damage accumulation model in which coordinated RNA regulation of PySLD5 promotes DNA repair, stabilizes replication forks and enhances overwintering survival.

Aging is associated with skeletal fragility driven by impaired bone remodeling, increased oxidative stress, and the accumulation of senescent cells. To determine whether ortho-vanillin (o-Vanillin) can alleviate age-related deficits in bone, we examined femoral bone microarchitecture, biomechanical properties, bone turnover, bone marrow adiposity, oxidative stress, DNA damage, osteocyte senescence, and femoral fracture healing in C57BL/6J mice. DEXA was additionally used to assess bone mineral density and content at the femur, tibia, spine, and whole body. Aged mice displayed substantial deterioration in femoral trabecular and cortical structure, reduced mechanical strength, diminished osteogenic activity, enhanced osteoclastogenesis, and increased marrow adiposity. Aging also elevated oxidative stress, lipid peroxidation, and DNA damage, and induced significant osteocyte senescence with upregulation of SASP factors. o-Vanillin administration attenuated these changes, improving femoral bone microarchitecture and strength, restoring osteoblast function, suppressing osteoclast activity and adipogenesis, reducing oxidative stress and γH2AX accumulation, and decreasing osteocyte senescence and SASP expression. In a mid-diaphyseal femoral fracture model, aged mice exhibited impaired callus formation and delayed healing, whereas o-Vanillin partially improved early cartilage formation, osteoblast activity, and mechanical strength of the healing callus. These findings demonstrate that o-Vanillin mitigates multiple age-related impairments in the femur and partially restores fracture healing capacity, supporting its potential as a senescence-targeting approach to improve skeletal health during aging.

Trichloroethylene induces cardiomyocyte senescence through an AhR-ROS-IL-1 axis and amplified by Wnt/β-catenin suppression.

Multidrug resistance (MDR) severely limits the efficacy of non-small lung cancer (NSCLC) treatment. Counteracting MDR is very difficult but highly necessary to extend the survival of MDR patients. This work aimed at establishing MDR NSCLC cellular models, to identify mechanisms responsible for their resistance to several treatments and new collateral sensitivity approaches to overcome MDR. Two paclitaxel resistant cell sublines (A549-CDR1 and A549-CDR2) were established, by treating A549 cells with increasing concentrations of paclitaxel. The proteomic profile (liquid chromatography-mass spectrometry) of these sublines was assessed as well as their MDR phenotype by evaluating response to several chemotherapeutic drugs (Sulforhodamine B assay) and the expression levels (Western Blotting) and activity (Rhodamine-123 accumulation assay) of ATP-binding cassette (ABC) transporter proteins. Cell death, reactive oxygen species (ROS) production (flow cytometry) and DNA damage levels (Comet assay and Western Blotting) were also evaluated prior to and following treatments with several drugs. The two established paclitaxel resistant cell sublines exhibited distinct proteomic profiles, although both presented a MDR phenotype, confirmed by cross-resistance to other chemotherapeutic drugs and increased expression levels and activity of ABC transporter proteins. They presented lower proliferation, higher ROS levels and increased DNA damage levels. These MDR cells were more sensitive than their parental cells to DNA damaging drugs that are not P-glycoprotein (P-gp) substrates, thus presenting collateral sensitivity to such drugs. The established NSCLC MDR cell lines are promising models to understanding mechanisms associated with MDR and exploiting collateral sensitivity approaches to overcome MDR in NSCLC.

Liver stem cell tumorigenesis in gilthead sea bream induced by B[a]P toxicity: In vitro insights.

Pharmacological inhibition of histone deacetylase 6 and DNA damage repair enhances radiosensitivity in melanoma.

Si-Jun-Zi-Tang potentiates temozolomide's anti-melanoma efficacy and reduces its hepatotoxicity.

Perfluoroalkyl and polyfluoroalkyl substances (PFAS), synthetic and resistant to degradation, are present at trace levels in municipal drinking water. PFAS exposure is associated with female infertility and developmental anomalies, yet how these compounds influence ovarian function and embryogenesis is not understood. Thus, the impact of exposure to PFAS via drinking water on oocyte viability and embryo development was examined. The local tap water was found to contain ∼3ng/L PFAS, primarily PFOS, PFOA, and PFHxS. Female mice were then given purified water containing 5ng/L or 50ng/L of these same three PFAS compounds or drinking fountain (tap) water for 4 weeks or 6 months. Ovulation, oocyte quality, embryo development and fetal weight were analyzed across three generations. Embryos from PFAS-exposed females (5ng/L or 50ng/L PFAS or tap water) exhibited impaired mitochondrial function, DNA damage and fewer cells, and reduced fetal weight. Embryo phenotypes were similar whether females were PFAS-exposed for 4 weeks, 6 months or just the first 4 weeks of the 6 months. Offspring drank purified water, yet fertility analysis showed similar embryonic and neonatal phenotypes in the F1 'daughters' of the PFAS-exposed females, and in the embryos of F2 females ('granddaughters' of PFAS-exposed females). To determine causality and whether defects are reversible, embryos were treated mitochondria-modulating compounds, with responses indicating that PFAS exposure irreversibly impairs key aspects of mitochondrial function. These findings identify cellular targets and mechanisms by which PFAS disrupt female fertility; reveal that PFAS cause intergenerational changes in mammalian embryos; and have important implications for water quality policies.

Developing a novel binuclear copper complex for enhanced cellular copper uptake and cancer treatment.

6PPD impairs liver growth through inflammatory pathways: Insights from zebrafish and human cell models.

The most widely accepted hypothesis for glioblastoma development posits that glioblastoma stem-like cells (GSCs) play a central role in tumor initiation, recurrence, and resistance to both chemotherapy and radiotherapy. We and others previously showed the importance of Mesenchyme Homeobox 2 (MEOX2) in supporting GSC survival and metabolism. In the present work, we demonstrate that MEOX2 also promotes DNA damage repair and contributes to resistance against genotoxic therapies in GSCs. Using a GLICO (GLioblastoma Cerebral Organoid) model, we show that MEOX2 knockdown impairs tumor growth and increases sensitivity to temozolomide (TMZ). Mechanistically, we find that MEOX2 depletion in 2D culture systems compromises genomic stability and impairs DNA repair. Co-immunoprecipitation and mass spectrometry analyses identified poly ADP-ribose polymerase 1 (PARP1) as a novel MEOX2 interactor. Consistent with this, MEOX2-depleted cells exhibit reduced PARylation levels and increased sensitivity to the PARP1 inhibitor Talazoparib, highlighting a potential therapeutic vulnerability. Altogether, our findings reveal a previously unrecognized role for MEOX2 in the DNA damage response of GSCs, particularly in promoting survival and recovery after chemotherapy and ionizing radiation. These results also suggest that MEOX2 functions as a partner of PARP1 and may represent a promising therapeutic target in GBM.

Conditioned medium from 1-nitropyrene induced THP-1 foam cells promotes pro-tumorigenesis in lung epithelial cells.

Imeglimin is a first-in-class oral antidiabetic that enhances glucose-induced insulin secretion and improves insulin resistance. Although imeglimin has been shown to exert protective effects on β-cells and hepatocytes partly by reducing the production of reactive oxygen species, its renoprotective effects remain largely unknown. In this study, we evaluated the effects of imeglimin on the kidneys using a mouse model of acute kidney injury induced by ischemia-reperfusion injury. Imeglimin significantly attenuated the increase in serum creatinine and blood urea nitrogen levels, as well as histological kidney injury. Gene ontology analysis of differentially expressed genes identified by RNA-sequencing of kidney tissues revealed that pathways related to inflammation were enriched in genes downregulated by imeglimin, whereas lipid metabolism and regulation of sodium ion transport were among the top enriched categories for genes upregulated by imeglimin. Moreover, ischemia-induced increase in the number of γH2AX-positive nuclei in proximal tubules was significantly suppressed by imeglimin. In addition, imeglimin inhibited increase in reactive oxygen species levels in human proximal tubule cells induced by transient hypoxia. These results indicate that imeglimin protects the kidney from ischemia-reperfusion injury by attenuating inflammatory responses and DNA damage, thereby maintaining gene expression associated with renal function. This protective effect may be partly mediated by a reduction in reactive oxygen species production. The potential of imeglimin to provide clinically meaningful protection against kidney complications warrants further investigation, considering the protective effects observed in ischemia-reperfusion injury.

Microplastics (MPs) and nanoplastics (NPs) have emerged as pollutants in aquatic ecosystems, resulting in several detrimental consequences for aquatic animals, particularly fish. Fish is a fundamental and economical food source, abundant in animal protein as well as micronutrients. Exposure of fish to MPs and NPs generates reactive oxygen species and induces oxidative stress, inflammation, and DNA damage, while also altering gut microbiota, thus diminishing fish development and quality. Additionally, the accumulation of MPs and NPs in aquatic habitats may reach the human body through the consumption of polluted fish, potentially leading to significant health consequences. Programmed cell death (PCD) is a genetically controlled process of autonomous and controlled cell death that maintains homeostasis and facilitates development. PCD is crucial in the pathological mechanisms of toxicity generated by MPs and NPs. Although research on PCD in MPs and NPs toxicity is limited, it is crucial to discover key molecules and understand their regulatory roles for better disease prevention and management. This comprehensive review aims to delineate and elaborate on the emerging role of different PCD mechanisms, including pyroptosis, apoptosis, necroptosis, autophagy, ferroptosis, cuproptosis, oxeiptosis, and PANoptosis, in the pathogenesis of toxicity generated by MPs and NPs in freshwater fish.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by steatosis, inflammation, hepatocellular injury and fibrosis, with the capacity to progress to cirrhosis and hepatocellular carcinoma. Recent evidence highlights cellular senescence, particularly in hepatic stellate cells (HSCs) as a key regulator of MASH pathogenesis. Senescent HSCs exhibit a context-dependent duality whereby, while transient senescence limits fibrosis through cell-cycle arrest, matrix degradation and enhanced immune clearance, persistent senescence under chronic metabolic and inflammatory stress drives disease progression. Through an expanded senescence-associated secretory phenotype (SASP), senescent HSCs exacerbate inflammation, promote extracellular matrix deposition, alter immune responses and facilitate malignant transformation. The present review summarizes the molecular mechanisms inducing HSC senescence, including lipotoxicity, oxidative stress, DNA damage, mitochondrial dysfunction and impaired autophagy. The mechanisms by which SASP factors mediate crosstalk between senescent HSCs and other cell types are discussed, including hepatocytes, macrophages, T cells and natural killer cells, collectively altering the inflammatory and fibrotic microenvironment of MASH. Finally, emerging therapeutic strategies targeting cellular senescence are highlighted, such as senolytics, senomorphics and biomarker-guided interventions, which may offer promising avenues for modifying the course of MASH and preventing disease progression.