DNA Oxidative Stress Research Articles

Gold nanoparticles as innovative therapeutics for oral mucositis: A review of current evidence.

Oral mucositis (OM) remains a debilitating side effect in patients undergoing cancer therapy. DNA damage and oxidative stress generated by radiation and/or chemotherapy activate key inflammatory pathways, ultimately resulting in the destruction of the epithelial barrier, leading to microbial colonization, and ulceration. These ulcerative lesions are often extremely painful, compromising nutrition and oral hygiene, requiring intravenous nutritional support, resulting in longer periods of hospitalization and increased cost. Ulcers often increase the risk of secondary infection, disrupting cancer therapy and patient prognosis. Despite these issues, there is no approved therapy to mitigate OM. Ultrasmall (< 10nm) spherical gold nanoparticles (AuNPs) with low toxicity offer unique size- and surface chemistry-dependent anti-inflammatory and antioxidant properties. However, physicochemical design of AuNPs, including size, capping agent, and surface charge critically influence their colloidal stability, toxicity, and therapeutic efficacy. AuNP below 10nm demonstrate increased therapeutic efficacy due to the high surface area-to-volume ratio, however, particles smaller than 2nm also show increased potential for inducing cellular death. Furthermore, anionic capping agents make AuNPs less toxic with increased anti-inflammatory response, while cationic particles are potent antimicrobials but toxic. Thus, surface chemistry modulation is a promising strategy to design AuNPs (< 10nm) as potential therapeutic agents for OM. This review provides a comprehensive overview of the OM pathophysiology, discusses current interventional concepts, critically analyses the existing literature on AuNP as an anti-inflammatory, antioxidant, and antimicrobial agent and highlights the benefits and challenges associated with using AuNPs as a therapeutic agent against OM.

Apigenin attenuates cisplatin-induced hair cell damage in the zebrafish lateral line

Cisplatin, a widely used chemotherapy drug, is notorious for causing ototoxicity, which leads to irreversible sensorineural hearing loss by damaging cochlear sensory hair cells (HCs), spiral ganglion neurons (SGNs), and the stria vascularis (SV). Mechanisms include DNA adduct formation, mitochondrial dysfunction, oxidative stress, and inflammation, ultimately triggering cell death pathways like apoptosis, necroptosis, pyroptosis, or ferroptosis. Apigenin, a natural flavonoid found in various foods and beverages, possesses antioxidant, anti-inflammatory, and anti-tumor properties. Despite these benefits, its potential to mitigate cisplatin-induced ototoxicity remains unexplored. To investigate, we administered varying concentrations of apigenin (1 μM, 20 μM, 100 μM, and 250 μM) alongside cisplatin (200 μM) to zebrafish larvae at 5 days post fertilization. Cisplatin significantly reduced lateral line HCs, impacting auditory function as shown in startle response tests. However, co-administration with apigenin preserved lateral line HCs and mitigated cisplatin-induced hearing loss. In larvae exposed to cisplatin, TUNEL assay confirmed significant HCs apoptosis, which apigenin effectively countered by suppressing reactive oxygen species accumulation in lateral line HCs. RNA-seq analysis highlighted apigenin's role in modulating apoptosis-related pathways, supporting its protective effects against cisplatin-induced ototoxicity. These findings underscore apigenin's potential as a crucial protective agent against cisplatin-induced ototoxicity, meriting further investigation for clinical applications.

The genotoxicity effects and oxidative stress of common volatile and injectable anesthesia drugs on peripheral blood during irradiation of BALB/c mice

IntroductionIonizing radiation (IR) is well-known for its genotoxic and cytotoxic effects. Additionally, anesthesia has been shown to cause various side effects, including genotoxicity. This study aims to evaluate the DNA damage and oxidative stress resulting from exposure to both anesthesia and IR. MethodsSeventy BALB/c male mice were divided into 14 identical groups and anesthetized using three different inhalation anesthetics (isoflurane, sevoflurane, and halothane) and three different injectable anesthetics (propofol, ketamine, and thiopental). We also evaluated combinations of these anesthetic drugs with 1 Gy IR. DNA damage in white blood cells was assessed using the alkaline comet assay at 0, 2, and 24 h after treatment. Additionally, oxidative stress in blood samples was measured 6 h post-treatment. ResultsThe percentage of DNA in the tail and fragmented nuclei after 2 and 24 h was significantly higher in the groups given volatile anesthetics compared to the propofol and thiopental groups (P<0.05). Furthermore, oxidative stress levels were also significantly higher in the volatile anesthetic groups (P<0.05). When combined with IR, the volatile anesthetics and ketamine resulted in increased genotoxicity and significantly higher oxidative stress compared to the group exposed only to IR (P<0.05). In contrast, propofol and thiopental did not lead to a significant increase in genotoxicity or oxidative stress compared to the control group (P>0.07). ConclusionCombining volatile anesthetic drugs and ketamine with 1 Gy irradiation resulted in higher levels of toxic effects and oxidative stress, although this combination did not produce a synergistic effect. Additionally, the combination of propofol and thiopental with IR did not show a significant difference compared to the irradiated-only group in both the alkaline comet and oxidative stress assays.

Improved photoprotection in the UVA/visible radiation boundary region is essential to prevent DNA damage, oxidative stress and gene expression changes in human skin

AbstractBackgroundStudies have demonstrated the potential for damage caused by exposure to radiation at the UVR/visible border region (380–410 nm) and beyond. This includes potentially mutagenic delayed DNA damage, increased gene expression related to photoageing and inflammation, pigmentation and the production of reaction oxygen species. Photoprotection in this region is limited, with a focus on shorter, more energetic UVR regions.ObjectivesTo assess the ability of two sunscreens for their ability to prevent photodamage in the UVA/visible region. Both sunscreens were labelled as SPF 15 and would meet requirements for labelling as UVA protective in the EU and USA. Their ingredients were identical apart from the addition of bis‐ (diethylaminohydroxybenzoyl benzoyl) piperazine (BDBP), a recently approved organic filter that absorbs between 350 and 425 nm.MethodsSunscreens were assessed in vitro in human cell lines and in vivo in healthy human volunteers (Fitzpatrick skin type I–II volunteers). Endpoints were assessed including oxidative stress, gene expression and DNA damage.ResultsThe formulation including the new filter provided significantly more protection than the conventional sunscreen for almost all endpoints tested. The conventional formulation provided some protection compared to unprotected skin or placebo control.ConclusionsThis study demonstrates the requirement for improved photoprotection at the UVR‐visible border region and the importance of assessing sunscreens across a broader range of wavelengths than currently approved protocols require.

Abstract A016: Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality

Abstract Non-small cell lung cancer (NSCLC) is a primary type of lung cancer and a leading cause of cancer-related mortality worldwide. The Warburg effect, characterized by increased glycolysis and reduced oxidative phosphorylation, is a hallmark of NSCLC and presents a therapeutic target. Annonacin, a natural compound found in fruits from the Annonaceae family, interferes with oxidative phosphorylation by inhibiting mitochondrial complex I. 2-deoxy-d-glucose (2DG), a glucose analog, disrupts glycolysis. This study examines the effects of Annonacin and 2DG on NSCLC A549 cells, both individually and in combination, with the hypothesis that inhibiting both metabolic pathways simultaneously will lead to more effective cancer treatment. In addition, we explored how these treatments might alter the tumor microenvironment, oxidative stress, and effects on normal epithelial bronchial cells. A549 NSCLC cells were exposed to different concentrations of Annonacin (0, 1, 2, 4, 6 µM) and 2DG (0,1.25, 2.5, 5, 10 mM), separately and together. Cell viability was measured using the MTT assay. Genotoxicity was assessed through the Comet Assay, and oxidative stress was evaluated by measuring superoxide dismutase and glutathione peroxidase activities. The long-term ability of the cells to proliferate was tested using colony-forming assays. The NL20 bronchial epithelial cell line was tested as a parallel control. Both Annonacin and 2DG showed a dose-dependent ability to kill A549 cells. However, when used together, these substances had a stronger effect, significantly lowering the number of surviving cells compared to when each was used alone. The response of this combination treatment on genotoxicity using Comet Assay is being pursued. Changes in oxidative stress responses were found, as shown by the altered superoxide dismutase and glutathione peroxidase enzyme activities. The ability of A549 cells to form colonies was greatly reduced following combination treatment, indicating a reduction in their long-term proliferative capacity. The combination of Annonacin and 2DG effectively inhibits the growth of NSCLC A549 cells by targeting their metabolic weaknesses, which may lead to increased DNA damage and oxidative stress. These results suggest simultaneous targeting glycolysis and oxidative phosphorylation could be a promising new approach for treating NSCLC. Future in vivo studies will evaluate this combination in live models and can offer insights into efficacy and possible translation to clinical application. Citation Format: Bhoj Raj Bhattarai, Cora Teets, Avinash Tope. Targeting metabolic vulnerability of non-small cell lung cancer with annonacin and 2-deoxy-d-glucose in individual and combination modality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A016.

Ameliorative impacts of carvacrol on DNA integrity, oxidative stress, and sperm quality in asthenozoospermic infertile individuals during cryopreservation.

Nowadays, the cryopreservation process can produce reactive oxygen species (ROS), which cause damage to the motility, cell membrane, and DNA integrity of sperm. This study is aimed at evaluating the impact of carvacrol, as a powerful antioxidant, on sperm features and improving oxidative stress throughout the cryopreservation procedure. In this prospective study, semen samples from 25 patients with asthenozoospermia were separated into three groups: fresh, freezing, and freezing + carvacrol (a dose of 100µM). The subsequent parameters were evaluated using standard methods in all three groups: sperm motility according to WHO criteria, sperm morphology using Papanicolaou staining, sperm viability with eosin-nigrosin staining, DNA integrity with acridine orange staining, levels of antioxidant enzymes (catalase, glutathione, and superoxide dismutase), total antioxidant capacity (TAC), and malondialdehyde (MDA) using ELISA. Also, DNA fragmentation was analyzed by the SDFA kit, and mitochondrial membrane potential (MMP) was assessed by rhodamine staining. Average sperm viability, motility, mitochondrial membrane potentiality, integrity of sperm membrane, and antioxidant enzyme levels are meaningfully reduced in the freezing group in contrast to the control group. The freezing group showed a meaningful rise in the mean MDA levels and DNA fragmentation compared to the control group. In the freezing group supplemented with carvacrol, a meaningful rise could be visible in mean percentages of viability, motility, and antioxidant enzyme levels, whereas mean levels of MDA and DNA fragmentation meaningfully declined in contrast to the freezing group. The results demonstrate that carvacrol, a potent antioxidant, offers significant protection against the loss generated by the freeze-thaw procedure, thereby improving sperm quality.

Isofraxidin alleviated radiation-induced testicular damage via the Nrf2/HO-1-NLRP3/ASC Axis

OBJECTIVE: Radiotherapy is used to treat patients with tumors; however, radiation (IR)-induced testicular injury, which has no effective treatment approved in clinical practice, significantly influences their prognosis and quality of life. The protective effects and underlying mechanisms of action of isofraxidin (IF) against IR-induced testicular injury were investigated. Methods: A mouse testis injury model was established using 5 Gy irradiation. H&amp;E staining, immunofluorescence staining, and enzyme-linked immunosorbent assay were used to measure DNA damage, apoptosis, inflammatory reactions, and oxidative stress in the testes of mice after irradiation. The effectiveness of IF irradiation on testicular injury was evaluated, and the mechanisms of the related oxidative stress and inflammatory response pathways are discussed. Results: IF can improve IR-induced testicular injury by inhibiting the increased levels of DNA damage, apoptosis rate, oxidative stress, and inflammatory factors. The radioprotective effects of IF on testicular injury are mediated by the stimulation of Nrf2/HO-1 or suppression of NLRP3 inflammasome signaling pathways. In addition, crosstalk between the Nrf2/HO-1 and NLRP3 inflammasome signaling pathways was elucidated, in which the inhibition of the NLRP3 inflammasome was mediated by the activation of Nrf2 signaling with IF upon IR exposure. Conclusion: IF can be a potent radioprotective agent to mitigate testicular damage, and may provide a new therapeutic option to alleviate the side effects of radiotherapy in male patients with tumors.

CSIG-14. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS THROUGH THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.

CSIG-15. ACROLEIN INDUCES THE MIR-30A-5P/NCAM AXIS VIA THE AKT/GSK3Β/Β-CATENIN PATHWAY, PROMOTING GLIOMA PROGRESSION

Abstract Glioblastoma (GBM), the most aggressive brain tumor, exhibits resistance to treatment and thrives in low-oxygen (hypoxic) environments, leading to the accumulation of reactive oxygen species (ROS). Hypoxia activates the hypoxia-inducible factor (HIF)-1α pathway, enhancing tumor malignancy. Acrolein, a reactive aldehyde produced during lipid peroxidation in hypoxia, induces toxicity through DNA damage, inflammation, mitochondrial dysfunction, and oxidative stress. Our previous study found elevated acrolein levels in hypoxic glioma cells and linked acrolein-induced DNA damage (Acr-dG) with poor GBM prognosis. However, the role of acrolein in GBM progression remains unclear. This study aims to elucidate the impact of acrolein on GBM. In vitro experiments demonstrated acrolein production under hypoxia, which increased glioma cell migration and spheroid formation. RNA sequencing identified five affected pathways: cell adhesion molecules, PI3K-AKT signaling, ECM-receptor interaction, MAPK signaling, and neuroactive ligand-receptor interaction. Acrolein downregulated NCAM (neural cell adhesion molecule) via the miR-30a-5p-AKT-GSK3β/β-catenin axis in GBM cell lines and patient-derived cells. Overexpressing NCAM reduced cell migration and spheroid formation. Lower NCAM levels in GBM tissues correlated with poor patient survival. This study suggests the potential of NCAM as a therapeutic target for GBM and provides insights into early detection and treatment strategies for this malignancy.

Electronegative ApoCIII-Rich HDL promotes cellular damage and vascular aging

Abstract Background Experimental studies attributing HDL a cardioprotective effect are challenged by well-designed randomized controlled trials showing largely neutral results, which might be related to more recent observations that certain HDL particles exert detrimental effects. This study explores the effects of electronegative HDL on cellular damage and vascular aging. Using anion-exchange chromatography, HDL was divided into five subclasses (H1 to H5) based on increasing electronegativity. Compared to the health-promoting H1, the most electronegative subclass, H5 contains significantly higher levels of ApoCIII and triglycerides (TG). Purpose Herein, we aim to explore the cellular and molecular mechanisms underpinning H5-induced pathology in human umbilical vein vascular endothelial cells (HUVECs), which may accelerate vascular aging preceding the development of atherosclerotic cardiovascular disease (ASCVD). Methods H1 and H5 were isolated from patients with metabolic syndrome (MetS). To gauge the impact of H5 on vascular integrity, HUVECs were treated with solvent, H1, or H5 at concentrations of 25, 50, or 100 µg/mL. Cell viability and apoptosis were evaluated using the MTT assay and PI/Calcein fluorescent staining, respectively. Immunofluorescence staining and immunoblotting, focusing on 8-oxodG, P53, and β-gal, proxies of DNA damage and cellular senescence, were performed. Senescence-associated secretory phenotype (SASP) analysis was done to elucidate the senescent mechanism. By harnessing Mitosox imaging reactive oxygen species (ROS) synthesis was monitored. Finally, unbiased lipid- and transcriptomics were used to identify lipid components potentially involved in H5 signaling. Results As compared to controls, MetS patients exhibited more electronegative HDL particles, as indicated by increased H5 (1.604±0.410% vs 4.598±4.712%, P=0.0016). Remarkable elevations were noted in individuals with severe clinical complications, as shown in the representative patient with left ventricular hypertrophy, chronic coronary syndrome, and heart failure (Fig. 1). In HUVECs, H5 but not H1 reduced cell viability and increased apoptosis in a concentration-dependent manner. In parallel, H5 but not H1 induced cell aging, ROS production, and DNA damage, with SASP cytokines including IL-1β, IL-6, CCL2, TNF-α, and γH2AX (Fig. 1). Notably, compared to H1, H5 exhibited high contents of various TG species, impairing H5’s anti-inflammatory and antioxidant capacities, along with reductions in several phosphatidylcholines that may constitute essential cell membrane structural components, as evidenced by lipidomic studies (Fig. 2). Conclusion H5, the most electronegative and dysfunctional HDL subfraction, is capable of inducing DNA damage, oxidative stress, and senescence in vascular ECs. Its notable elevation in patients with MetS highlights a previously unrecognized etiology, shedding light on how electronegative HDL may contribute to and expedite ASCVD.Fig 1Fig 2

Elevated DNA Damage without signs of aging in the short-sleeping Mexican Cavefish.

Dysregulation of sleep has widespread health consequences and represents an enormous health burden. Short-sleeping individuals are predisposed to the effects of neurodegeneration, suggesting a critical role for sleep in the maintenance of neuronal health. While the effects of sleep on cellular function are not completely understood, growing evidence has identified an association between sleep loss and DNA damage, raising the possibility that sleep facilitates efficient DNA repair. The Mexican tetra fish, Astyanax mexicanus provides a model to investigate the evolutionary basis for changes in sleep and the consequences of sleep loss. Multiple cave-adapted populations of these fish have evolved to sleep for substantially less time compared to surface populations of the same species without identifiable impacts on healthspan or longevity. To investigate whether the evolved sleep loss is associated with DNA damage and cellular stress, we compared the DNA Damage Response (DDR) and oxidative stress levels between A. mexicanus populations. We measured markers of chronic sleep loss and discovered elevated levels of the DNA damage marker γH2AX in the brain, and increased oxidative stress in the gut of cavefish, consistent with chronic sleep deprivation. Notably, we found that acute UV-induced DNA damage elicited an increase in sleep in surface fish but not in cavefish. On a transcriptional level, only the surface fish activated the photoreactivation repair pathway following UV damage. These findings suggest a reduction of the DDR in cavefish compared to surface fish that coincides with elevated DNA damage in cavefish. To examine DDR pathways at a cellular level, we created an embryonic fibroblast cell line from the two populations of A. mexicanus . We observed that both the DDR and DNA repair were diminished in the cavefish cells, corroborating the in vivo findings and suggesting that the acute response to DNA damage is lost in cavefish. To investigate the long-term impact of these changes, we compared the transcriptome in the brain and gut of aged surface fish and cavefish. Strikingly, many genes that are differentially expressed between young and old surface fish do not transcriptionally vary by age in cavefish. Taken together, these findings suggest that cavefish have developed resilience to sleep loss, despite possessing cellular hallmarks of chronic sleep deprivation.

APE1 is a master regulator of the ATR-/ATM-mediated DNA damage response

To maintain genomic integrity, cells have evolved several conserved DNA damage response (DDR) pathways in response to DNA damage and stress conditions. Apurinic/apyrimidinic endonuclease 1 (APE1) exhibits AP endonuclease, 3′-5′ exonuclease, 3′-phosphodiesterase, and 3′-exoribonuclease activities and plays critical roles in the DNA repair and redox regulation of transcription. However, it remains unclear whether and how APE1 is involved in DDR pathways. In this perspective, we first updated our knowledge of APE1's functional domains and its nuclease activities and their specific associated substrates. We then summarized the newly discovered roles and mechanisms of action of APE1 in the global and nucleolar ATR-mediated DDR pathway. While the ATM-mediated DDR is well known to be activated by DNA double-strand breaks and oxidative stress, here we provided new perspectives as to how ATM DDR signaling is activated by indirect single-strand breaks (SSBs) resulting from genotoxic stress and defined SSB structures, and discuss how ATM kinase is directly activated and regulated by its activator, APE1. Together, accumulating body of new evidence supports the notion that APE1 is a master regulator protein of the ATR- and ATM-mediated DDR pathways. These new findings of APE1 in DDR signaling provide previously uncharacterized but critical functions and regulations of APE1 in genome integrity.

The Influence of Circadian Rhythms on DNA Damage Repair in Skin Photoaging.

Circadian rhythms, the internal timekeeping systems governing physiological processes, significantly influence skin health, particularly in response to ultraviolet radiation (UVR). Disruptions in circadian rhythms can exacerbate UVR-induced skin damage and increase the risk of skin aging and cancer. This review explores how circadian rhythms affect various aspects of skin physiology and pathology, with a special focus on DNA repair. Circadian regulation ensures optimal DNA repair following UVR-induced damage, reducing mutation accumulation, and enhancing genomic stability. The circadian control over cell proliferation and apoptosis further contributes to skin regeneration and response to UVR. Oxidative stress management is another critical area where circadian rhythms exert influence. Key circadian genes like brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) modulate the activity of antioxidant enzymes and signaling pathways to protect cells from oxidative stress. Circadian rhythms also affect inflammatory and immune responses by modulating the inflammatory response and the activity of Langerhans cells and other immune cells in the skin. In summary, circadian rhythms form a complex defense network that manages UVR-induced damage through the precise regulation of DNA damage repair, cell proliferation, apoptosis, inflammatory response, oxidative stress, and hormonal signaling. Understanding these mechanisms provides insights into developing targeted skin protection and improving skin cancer prevention.

Laminin-α2 chain deficiency in skeletal muscle causes dysregulation of multiple cellular mechanisms.

LAMA2, coding for the laminin-α2 chain, is a crucial ECM component, particularly abundant in skeletal muscle. Mutations in LAMA2 trigger the often-lethal LAMA2-congenital muscular dystrophy (LAMA2-CMD). Various phenotypes have been linked to LAMA2-CMD; nevertheless, the precise mechanisms that malfunction during disease onset in utero remain unknown. We generated Lama2-deficient C2C12 cells and found that Lama2-deficient myoblasts display proliferation, differentiation, and fusion defects, DNA damage, oxidative stress, and mitochondrial dysfunction. Moreover, fetal myoblasts isolated from the dy W mouse model of LAMA2-CMD display impaired differentiation and fusion in vitro. We also showed that disease onset during fetal development is characterized by a significant down-regulation of gene expression in muscle fibers, causing pronounced effects on cytoskeletal organization, muscle differentiation, and altered DNA repair and oxidative stress responses. Together, our findings provide unique insights into the critical importance of the laminin-α2 chain for muscle differentiation and muscle cell homeostasis.

Effects of High-Linear-Energy-Transfer Heavy Ion Radiation on Intestinal Stem Cells: Implications for Gut Health and Tumorigenesis.

Heavy ion radiation, prevalent in outer space and relevant for radiotherapy, is densely ionizing and poses a risk to intestinal stem cells (ISCs), which are vital for maintaining intestinal homeostasis. Earlier studies have shown that heavy-ion radiation can cause chronic oxidative stress, persistent DNA damage, cellular senescence, and the development of a senescence-associated secretory phenotype (SASP) in mouse intestinal mucosa. However, the specific impact on different cell types, particularly Lgr5+ intestinal stem cells (ISCs), which are crucial for maintaining cellular homeostasis, GI function, and tumor initiation under genomic stress, remains understudied. Using an ISCs-relevant mouse model (Lgr5+ mice) and its GI tumor surrogate (Lgr5+Apc1638N/+ mice), we investigated ISCs-specific molecular alterations after high-LET radiation exposure. Tissue sections were assessed for senescence and SASP signaling at 2, 5 and 12 months post-exposure. Lgr5+ cells exhibited significantly greater oxidative stress following 28Si irradiation compared to γ-ray or controls. Both Lgr5+ cells and Paneth cells showed signs of senescence and developed a senescence-associated secretory phenotype (SASP) after 28Si exposure. Moreover, gene expression of pro-inflammatory and pro-growth SASP factors remained persistently elevated for up to a year post-28Si irradiation. Additionally, p38 MAPK and NF-κB signaling pathways, which are critical for stress responses and inflammation, were also upregulated after 28Si radiation. Transcripts involved in nutrient absorption and barrier function were also altered following irradiation. In Lgr5+Apc1638N/+ mice, tumor incidence was significantly higher in those exposed to 28Si radiation compared to the spontaneous tumorigenesis observed in control mice. Our results indicate that high-LET 28Si exposure induces persistent DNA damage, oxidative stress, senescence, and SASP in Lgr5+ ISCs, potentially predisposing astronauts to altered nutrient absorption, barrier function, and GI carcinogenesis during and after a long-duration outer space mission.

Ultraviolet Light Causes Skin Cell Senescence: From Mechanism to Prevention Principle.

The skin is an effective protective barrier that significantly protects the body from damage caused by external environmental factors. Furthermore, skin condition significantly affects external beauty. In today's era, which is of material and spiritual prosperity, there is growing attention on skincare and wellness. Ultraviolet radiation is one of the most common external factors that lead to conditions like sunburn, skin cancer, and skin aging. In this review, several mechanisms of UV-induced skin cell senescence are discussed, including DNA damage, oxidative stress, inflammatory response, and mitochondrial dysfunction, which have their own characteristics and mutual effects. As an illustration, mitochondrial dysfunction triggers electron evasion and the generation of more reactive oxygen species, leading to oxidative stress and the activation of the NLRP3 inflammasome, which in turn causes mitochondrial DNA (mt DNA) damage. Based on the current mechanism, suitable prevention and treatment strategies are proposed from sunscreen, dietary, and experimental medications respectively, aimed at slowing down skin cell aging and providing protection from ultraviolet radiation. The effects of ultraviolet rays on skin is summarized, offering insights and directions for future studies on mechanism of skin cell senescence, with an anticipation of discovering more effective prevention and cure methods.

Environmental Exposures and Cancer Risk: A Comprehensive Review

Environmental exposure is increasingly recognized as a significant cancer risk factor. This comprehensive review aims to provide an overview of current knowledge regarding the relationship between several environmental factors and the development of cancer. The complicated interactions between genetic predispositions and environmental factors in the etiology of cancer are highlighted in this study by looking at both known and newly discovered environmental carcinogens. The review covers a broad spectrum of environmental exposures, including occupational risks, dietary and physical activity habits, and toxins in the air and water. It also explores the molecular processes by which these exposures cause cancer, with particular attention to pathways including DNA damage, oxidative stress, and epigenetic changes. This review also discusses the differences in cancer risk associated with environmental exposures among various populations, highlighting the necessity of focused preventative and therapeutic measures. The results highlight how crucial it is to implement public health programs and regulatory regulations targeted at lowering environmental carcinogen levels and lessening their influence on the incidence of cancer. Considering an emphasis on developing precision medicine techniques and enhancing environmental health equality, future research directions are suggested further to clarify the complex links between the environment and cancer.

Changes in composition and concentration of differential metabolites in root exudates are associated with aluminum-tolerance of Ricinus communis under a high CO2 environment

Root exudates are the most direct performance for plants responding to adverse environments, and are also important media for materials exchange, energy transmission and information communication between the roots and rhizosphere. However, how plant roots and exudates respond to aluminum (Al) stress under elevated CO2 concentration (eCO2) is still unclear. Ricinus communis is a famous oilseed crop throughout the world, which has strong tolerance to metal contaminated soil. In the present study, root physiological changes and the exudates of this species under aluminum stress and eCO2 based on metabolomic were investigated. The results showed that high Al concentration stress significantly increased aluminum, MDA, proline, and soluble sugar contents, and decreased the dry weights and soluble protein concentration. Furthermore, eCO2 alleviated the inhibition of root growth under high Al stress by increasing the dry weights, antioxidant enzyme activities and decreasing the MDA content. Collectively, a total of 511 metabolites were detected in the castor exudates of which lipids, organic acids, and organic oxygen compounds occupied 40.82%, 17.78% and 12.54%, respectively. There were 83, 15, and 100 differential metabolites for high Al stress, eCO2 and the interaction of the two factors compared with the control. 12 differential metabolites were found under eCO2 and Al stress compared with Al stress alone. Under Al stress, TCA cycle, organic acids, and lipids metabolisms were inhibited; coumarins and carbohydrates conjugates were significantly up-regulated, which may help castor adapt to aluminum-contaminated conditions. Moreover, eCO2 increased the secretion of organic acids, fatty acyls, and carbohydrates to enhance the antioxidant capacity and root growth of castor under Al stress; eCO2 enhanced the TCA cycle, organic acids accumulation, lipids metabolism, biosynthesis of amino acids, pentose and glucuronate interconversions, and inhibited DNA oxidative stress of castor roots under Al stress. The present study provides new insights into the crucial role of root exudates in improving Al-tolerance of castor under eCO2.

Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review.

Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.

Prediction of immunotherapy response using mutations to cancer protein assemblies

While immune checkpoint inhibitors have revolutionized cancer therapy, many patients exhibit poor outcomes. Here, we show immunotherapy responses in bladder and non–small cell lung cancers are effectively predicted by factoring tumor mutation burden (TMB) into burdens on specific protein assemblies. This approach identifies 13 protein assemblies for which the assembly-level mutation burden (AMB) predicts treatment outcomes, which can be combined to powerfully separate responders from nonresponders in multiple cohorts (e.g., 76% versus 37% bladder cancer 1-year survival). These results are corroborated by (i) engineered disruptions in the predictive assemblies, which modulate immunotherapy response in mice, and (ii) histochemistry showing that predicted responders have elevated inflammation. The 13 assemblies have diverse roles in DNA damage checkpoints, oxidative stress, or Janus kinase/signal transducers and activators of transcription signaling and include unexpected genes (e.g., PIK3CG and FOXP1) for which mutation affects treatment response. This study provides a roadmap for using tumor cell biology to factor mutational effects on immune response.