Chitosan-based biopolymers for radioprotection: Mechanisms and biomedical applications in radiotherapy - A review.

Hydroxysafflor yellow A protects against ischemic stroke-associated Weber syndrome by inhibiting oxidative stress and alleviating DNA damage.

Impact of Endogenous Melatonin Status on Perioperative Oxidative Stress in Pediatric Cardiac Surgery With Cardiopulmonary Bypass.

Abstract Neutrophils, the primary responders to inflammation in infection and cancer, exhibit precise chemotaxis to target sites. They also show functional plasticity in tumor progression, with distinct subsets exerting opposing effects—either fostering oncogenesis or mediating antitumor responses. Recently, the introduction of nanotherapeutics offers the opportunity to effectively augment the anti‐tumor effects of neutrophils and avoid the risk of tumor promotion during treatment. In this review, oncopromotion (cell proliferation, angiogenesis, immunodepression, and DNA injury), a combination of oncogenesis and promotion, and metastasis (transmigration and pre‐niche) conditions are used to summarize the tumorigenic effect of neutrophils. Regarding the tumor suppression mechanism of neutrophils, three “C” stages are further generalized that is, coordination, cytolysis, and chemosecretion. Neutrophils coordinate innate and adaptive immunity via cytokines and surface molecules, mediate antibody‐dependent cytotoxicity to disrupt cancer cell membranes, and secrete inflammatory factors to modulate ion channels and directly kill tumor cells. Capitalizing on neutrophils' chemotaxis and nanotherapeutic interactions, membrane encapsulation and whole‐cell mediation nanoplatforms are integrated to synthesize cutting‐edge advancements in neutrophil nanomedicines, particularly, multimechanistic anticancer strategies. Last but not least, an outlook for introducing AI aimed at improving the safety, scalability, and reproducibility of neutrophil‐based oncolytic nanotherapeutics is provided.

Ischemia-reperfusion (I/R) injury is a notable cause of tissue damage, particularly in patients with peripheral artery disease. Rivaroxaban is a novel oral anticoagulant that can reduce cardiovascular events. However, its potential antioxidant properties remain poorly understood. Therefore, the present study aimed to investigate the effect of rivaroxaban on oxidative DNA injury in a rat model of I/R injury by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels, a key biomarker of oxidative DNA injury. A total of 21 female Wistar albino rats were randomly divided into three groups, namely the sham, control (I/R) and rivaroxaban treatment (3 mg/kg/day) groups. Following treatment for 10 days, hind limb ischemia was induced in rats for 1 h, followed by reperfusion for 2 h. Subsequently, blood and skeletal muscle samples were collected and analyzed for oxidative stress markers, including 8-OHdG, glutathione (GSH), oxidized GSH and malondialdehyde (MDA), using ELISA and high-performance liquid chromatography. The results demonstrated that compared with those in the sham group, rats in the control group exhibited significantly elevated 8-OHdG, GSSG and MDA levels, coupled with decreased GSH levels. By contrast, treatment with rivaroxaban notably reversed the elevated 8-OHdG and MDA levels whilst restoring GSH levels compared with those in the control group, indicating an improved oxidative status. Overall, these findings suggested that in addition to its established anticoagulant properties, rivaroxaban can also protect against I/R-induced oxidative DNA injury.

Harnessing the HMnO2 nanoparticles as the DNA injury amplifier to improve the OXA-based trans-artery infusion chemotherapy.

Regular hookah smoking (Reg‐HS) has become a major global public health issue, linked to significant health risks, including kidney damage. A less frequent pattern of use, known as occasional hookah smoking (Occ‐HS), is also common; however, there has been little progress in understanding the direct impact of Occ‐HS on kidneys. To investigate how varying frequencies of HS inhalation affect the kidney, we exposed mice to nose‐only HS under two regimens, occasional (30 min once weekly) and regular (30 min five times per week) for a duration of 6 months. This study explored the impact on renal damage, inflammatory responses, oxidative stress levels, genotoxicity, and mitochondrial activity as well as the possible modulation of MAPK signaling pathway. Both Occ‐HS and Reg‐HS led to a marked elevations in plasma levels of urea and creatinine (p < 0.05–p < 0.0001). Additionally, concentrations of kidney injury molecule‐1 (KIM‐1) and neutrophil gelatinase‐associated lipocalin (NGAL) were significantly increased in both groups (p < 0.01–p < 0.0001). Notably, only the Reg‐HS regimen induced a substantial rise in plasma levels of indoxyl sulfate, cystatin C, and adiponectin (p < 0.01–p < 0.0001). Similarly, relative to the control group, mice subjected to Reg‐HS exposure exhibited significantly elevated levels of proinflammatory cytokines, tumor necrosis factor‐α, and interleukin‐6 (p < 0.0001). Exposure to either Occ‐HS or Reg‐HS caused significant increase in interleukin‐1β (p < 0.05, p < 0.0001), thiobarbituric acid reactive substances (TBARS; p < 0.05, p < 0.0001) compared with air‐exposed mice. Our findings revealed that Occ‐HS inhalation triggered only a decrease in superoxide dismutase (SOD) activity (p < 0.001). On the other hand, nitric oxide (NO; p < 0.001), SOD (p < 0.0001), and Glutathione (GSH; p < 0.0001) levels were significantly decreased in Reg‐HS group. Furthermore, DNA damage marker, 8‐Hydroxy‐2′‐deoxyguanosine was significantly augmented in both regimens (p < 0.0001). Exposure to both regimens resulted in significant elevation in mitochondrial complexes I, II and III, and IV (p < 0.0001). Increased expression of activation of mitogen‐activated protein kinases (MAPKs) was observed exclusively in the Reg‐HS group, as evidenced by increased levels of p‐JNK, p‐p38, and p‐ERK (p < 0.001–p < 0.0001). In conclusion, our study is the first to demonstrate that despite the significant differences in the amount of smoke inhaled, both Occ‐HS or Reg‐HS inhalation deteriorate kidney function and induce oxidative damage, inflammatory response, DNA injury, and mitochondrial impairment with modulation of the MAPK signaling. These findings highlight the importance of further research into the public health risks associated with occasional hookah smoking.

Background: Agents with free radical-scavenging functions may act as radiation modifiers, protectors, or mitigators. Methods: We investigated whether supplementation with resveratrol (RSV) in mice, at different times after the beginning of X-irradiation, may influence sperm count and quality during the irradiation and recovery. Results: Irradiation importantly decreased the sperm count. RSV supplemented with 1 Gy since 24 h increased sperm count. The combination of low doses increased, whereas the combination of high doses reduced DNA damage. Coadministration of two high doses since the eighth day significantly increased DNA damage and slightly increased sperm count. The supplementation of RSV during recovery was toxic to irradiated males. The sperm parameters were a little better in the absence of RSV. The degree of DNA injury of germ cells was importantly lower in groups combined with 1 Gy. Conclusions: Resveratrol counteracted the radiation-induced death of germ cells and improved the sperm count. RSV may function as radioprotector (before or during exposure) and radiomitigator (after exposure) of lethal effects in male gametes. The combination of high doses of irradiation with RSV over 24 h mitigated DNA damage. Contrarily, supplementation during recovery is not recommended since it may be toxic during long-lasting irradiation.

All cells possess mechanisms to maintain and replicate their genomes, whose integrity and transmission are constantly challenged by DNA damage and replication impediments. In eukaryotes, the protein kinase Ataxia-Telangiectasia and Rad3-related (ATR), a member of the phosphatidylinositol 3-kinase-like family, acts as a master regulator of the eukaryotic response to DNA injuries, ensuring DNA replication completion and genome stability. Here we aimed to investigate the functional relevance of the ATR homolog in the DNA metabolism of Leishmania major, a protozoan parasite with a remarkably plastic genome. CRISPR/cas9 genome editing was used to generate a Myc-tagged ATR cell line (mycATR), and a Myc-tagged C-terminal knockout of ATR (mycATRΔC-/-). We show that the nuclear localisation of ATR depends upon its C-terminus. Moreover, its deletion results in single-stranded DNA accumulation, impaired cell cycle control, increased levels of DNA damage, and delayed DNA replication re-start after replication stress. In addition, we show that ATR plays a key role in maintaining L. major’s unusual DNA replication program, where larger chromosomes duplicate later than smaller chromosomes. Our data reveals loss of the ATR C-terminus promotes the accumulation of DNA replication signal around replicative stress fragile sites, which are enriched in larger chromosomes. Finally, we show that these alterations to the DNA replication program promote chromosome instability. In summary, our work shows that ATR acts to modulate DNA replication timing, limiting the plasticity of the Leishmania genome.

All cells possess mechanisms to maintain and replicate their genomes, whose integrity and transmission are constantly challenged by DNA damage and replication impediments. In eukaryotes, the protein kinase Ataxia-Telangiectasia and Rad3-related (ATR), a member of the phosphatidylinositol 3-kinase-like family, acts as a master regulator of the eukaryotic response to DNA injuries, ensuring DNA replication completion and genome stability. Here we aimed to investigate the functional relevance of the ATR homolog in the DNA metabolism of Leishmania major, a protozoan parasite with a remarkably plastic genome. CRISPR/cas9 genome editing was used to generate a Myc-tagged ATR cell line (mycATR), and a Myc-tagged C-terminal knockout of ATR (mycATRΔC-/-). We show that the nuclear localisation of ATR depends upon its C-terminus. Moreover, its deletion results in single-stranded DNA accumulation, impaired cell cycle control, increased levels of DNA damage, and delayed DNA replication re-start after replication stress. In addition, we show that ATR plays a key role in maintaining L. major's unusual DNA replication program, where larger chromosomes duplicate later than smaller chromosomes. Our data reveals loss of the ATR C-terminus promotes the accumulation of DNA replication signal around replicative stress fragile sites, which are enriched in larger chromosomes. Finally, we show that these alterations to the DNA replication program promote chromosome instability. In summary, our work shows that ATR acts to modulate DNA replication timing, limiting the plasticity of the Leishmania genome.

Despite the extensive applicability of cadmium oxide nanoparticles (CdO NPs) in diverse fields, there is a prominent gap in our understanding of their toxicological impacts, particularly when using invertebrate insect model organisms. This study aimed to instigate this research gap by investigating the oxidative stress and genotoxicity effects of CdO NPs using Galleria mellonella as an insect model. We evaluated the immune response, oxidative stress, stress response proteins, detoxification enzymes, DNA damage, and cell viability following exposure to a single dose of CdO NPs. A comprehensive approach was conducted, combining biochemical, molecular, ultrastructural, and morphological analyses. Interestingly, the most pronounced effect of CdO NPs on larval mortality was observed at the lowest dose of 0.01 mg/g body weight. Also, EDX analysis demonstrated a substantial accumulation of cadmium in larval midgut tissues exposed to a single injection of CdO NPs compared to the control, leading to oxidative stress, disruption of antioxidant and detoxification defense systems as well as DNA injury, and increased apoptotic and necrotic cell death lead to the destruction of the larval intestinal barrier. Moreover, pathohistological and ultrastructural investigations inspected prominent alterations and anomalies in larval midgut epithelium, including vacuolization, degeneration of cytoplasmic organelles, distorted microvilli, along with obvious necrotic signs. This study not only contributes to filling the prevailing knowledge gap concerning the toxicity of CdO NPs but also stipulates valuable insights into their broader environmental impact, potentially updating future risk assessments and monitoring decisions regarding nanomaterial applications.

An independent association between insulin resistance and cancer has been consistently reported in humans. Patients with cancer display insulin resistance or its clinical manifestations, and this metabolic adaptation precedes the clinical diagnosis of cancer. Insulin resistance in cancer patients is associated with a metabolic switch from oxidative metabolism toward glycolysis that spares oxygen to be used in anabolic processes and facilitates the fast production of energy and intermediate metabolites required for the rapid proliferation of cancer cells. In malignant cells, glucose consumption via glycolysis occurs under normoxic conditions (aerobic glycolysis). Pathogenic mechanisms underlying insulin resistance in cancer patients include hypoxia-inducible factor-1 upregulation and overproduction of cytokines, such as interferon, interleukin-6, interleukin-18, and interleukin-1β. Deficit of 2-oxoglutarate (α-ketoglutarate) has been detected in cancer cells and may facilitate hypoxia-inducible factor-1 assembly and activity. Overproduction of cytokines in cancer patients follows activation of the immune system by abnormal nucleic acid variants. Anomalous DNA or RNA structures are recognized by immune sensors and stimulate signaling pathways that ultimately increase cytokine production. Likewise, interferon overproduction occurs in congenital disorders that feature ineffectively repaired DNA lesions, such as Werner syndrome, Bloom syndrome, mutations in DNA polymerase-δ1, and ataxia telangiectasia. These diseases cause simultaneous insulin resistance and a high tendency to develop cancer, highlighting the relationship between the two processes. Defectively repaired DNA injury endangers genomic integrity, predisposing to cancer, and activates the immune system to increase interferon production and subsequent insulin resistance. Hypoxia-inducible factor-1 and cytokines induce insulin resistance by suppressing peroxisome proliferator-activated-γ in the subcutaneous adipose tissue.

Reactive oxygen species (ROS)-induced DNA oxidative damage is a significant manifestation of oxidative stress in the body and is closely associated with the onset and progression of various diseases. Although Pyripyropene A (PPPA) exhibits anti-tumor and anti-inflammatory activities, its antioxidant and protective effects against DNA oxidative injury remain unclear. In this study, using a hydrogen peroxide-induced oxidative injury model of L02 cells, it was found that PPPA could significantly reduce intracellular ROS and malondialdehyde (MDA) levels, enhance the activities of catalase (CAT) and reduced glutathione (GSH), and increase the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) clearance rate, confirming its antioxidant effect. Comet assay showed a reduction in DNA breakage, and down-regulation of phosphorylated histone (γ-H2AX) and 8-hydroxydeoxyguanosine (8-oxodG), indicating that it effectively alleviates DNA oxidative injury. Meanwhile, the upregulated expression of poly ADP-ribose polymerase (PARP) suggests that PPPA may promote repair by activating the DNA damage response (DDR). This study systematically clarify for the first time that PPPA exerts a protective effect by synergistically antioxidizing, reducing DNA injury, and potentially activating repair pathways, providing a theoretical basis for its application in neoplasm and oxidative stress-related diseases.

ABSTRACTElite sports have become increasingly professionalized and personalized, with soccer players facing a high number of games per season. This trend presents significant challenges in optimizing training for peak performance and requires rigorous monitoring of athletes to prevent overload and reduce injury risks. The emerging field of epigenetic clocks offers promising new pathways for developing useful biomarkers that enhance training management. This study investigates the effects of intense physical activity on epigenetic age markers in professional soccer players across multiple games and during a championship season. We analyzed DNA methylation data from saliva samples collected before and after physical activity. Vigorous physical activity was found to rejuvenate epigenetic clocks, with significant decreases in DNAmGrimAge2 and DNAmFitAge observed immediately after games. Among player subgroups, midfielders exhibited the most substantial epigenetic rejuvenation effect following games. Additionally, the study suggests a potential link between DNA methylation patterns and injury occurrence. Overall, our study suggests that DNA methylation‐based biomarkers may have applications in monitoring athlete performance and managing physical stress.

The current study investigated the mitigating effects of thymoquinone (TQ) against high-fat diet (HFD)-mediated brain injury, cognitive and memory impairment, and the underlying mechanisms. Twenty-four adult male Wistar rats were divided into four groups of six rats each. Rats were fed HFD for 12 weeks to induce obesity. On the 9th week, TQ was administered orally to obese rats for four weeks. The effects of TQ were estimated by neurobehavioral testing, biochemical analysis, DNA damage, molecular docking, and histopathological examination of brains and visceral fat. TQ reduced body weight, body weight gain and adipocyte size, improved hyperlipidemia, and normalized the levels of leptin and adiponectin. TQ significantly attenuated the increase in HbA1c percent and insulin resistance. TQ decreased the accumulation of amyloid-β and tau proteins and improved the levels of neurotransmitters in the brains of obese rats. TQ-treated obese rats showed improved thickening of the pyramidal cell layer in the hippocampus and improved cognitive function and memory impairments. Molecular docking analysis indicated that TQ exhibited a marked affinity for inhibiting binding sites of tau and amyloid-β proteins. Furthermore, TQ controlled oxidative stress and enhanced the Nrf2 expression in the pyramidal cell layer and the activity of HO-1, SOD, and CAT in the brain. The restoration of redox balance by TQ was associated with normalization of inflammatory indicators and alleviation of DNA damage in the brains of HFD-treated animals. These changes contributed to the normalization of mitochondrial apoptotic pathway mediators (p53, Bcl-2, Bax, and caspase-3) and maintained the histological structure of the hippocampus. In conclusion, TQ attenuated brain injury, cognitive impairment, and memory deficit with improvement of body weight gain and metabolic status in obese rats through interrelated biological processes, including regulation of redox balance, inflammatory response, neurotransmitter equilibrium, and regression of DNA injury and apoptosis.

Despite the importance of o6-methylguanine-DNA methyltransferase (MGMT) (a DNA repair enzyme) in cancer cells, the impacts of MGMT in macrophages are still unknown. In mgmt null mice (mgmtflox/flox; LysM-Crecre/-; mgmt deletion only in macrophages), subcutaneous administration of MC38 (a murine colon cancer) induced smaller tumors with lower intratumoral CD206-positive cells (mostly M2-like macrophages) than the tumors in littermate controls (mgmt control) (mgmtfl/fl; LysM-Cre-/-), as indicated by immunohistochemistry and flow cytometry. Then, bone marrow-derived macrophages were incubated with lipopolysaccharide (LPS) (M1 polarization), IL-4 (M2 polarization), MC38-conditioned media (tumor-associated macrophages; TAMs), and control media (control). In comparison with control, mgmt was upregulated in all activated cells (M1, M2, and TAMs), with the most prominent in M1. Less prominent M1 pro-inflammation (lower IL-1β and iNOS expression) and M2 polarization (lower Arg-1 expression) in mgmt null macrophages compared with mgmt control were observed. The tumoricidal activity was demonstrated only in M1 (but not M2 and TAMs), and mgmt control M1 was more prominent than mgmt null M1, as evaluated by flow cytometry using flexible 780 viable dye. There was reduced maximal respiration (extracellular flux analysis) with more prominent cell injuries, as indicated by cell-free DNA, oxidative stress (malondialdehyde), and DNA break (phosphohistone H2AX immunohistochemistry), in TAMs from mgmt null when compared with mgmt control. In conclusion, TAM transformation required cell energy and induced DNA injury, which needed the MGMT enzyme for DNA repair. Without MGMT, the abundance of TAMs was too low to promote cancer growth. The use of MGMT inhibitors for cancers is encouraged.

Glutathione S-transferase pi (GSTpi) is a phase II detoxifying enzyme that plays key roles in cellular processes. In a previous study, we have reported that cell permeable Tat-GSTpi can protect dopaminergic neurons against cell death. However, the precise roles of GSTpi in inflammation remain to be elucidated. Thus, the objective of present study is to investigate the one of plausible protective mechanism involved anti-inflammatory effect of GSTpi using lipopolysaccharide (LPS)- and 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced macrophages and an animal model. It was revealed that cell permeable Tat-GSTpi fusion protein markedly reduced reactive oxygen species (ROS) and DNA injury in LPS-treated cells and transduced protein showed not only inhibition of the regulation of mitogen-activated protein kinase (MAPK) and Caspase-9, but also decrease of COX-2 and iNOS expressions. Furthermore, Tat-GSTpi ameliorated skin inflammation in an animal model by inhibition the COX-2, iNOS expression and cytokines. Those results indicate that GSTpi plays a role in antagonizing LPS- and TPA-induced inflammation, suggesting GSTpi has the potential to serve as a therapeutic treatment for inflammatory related diseases. [BMB Reports 2025; 58(6): 238-243].

Oxidative stress due to hyperglycemia damages the functions of retinal pigment epithelial (RPE) cells and is a major risk factor for diabetic retinopathy (DR). Paeoniflorin is a monoterpenoid glycoside found in the roots of Paeonia lactiflora Pall and has been reported to have a variety of health benefits. However, the mechanisms underlying its therapeutic effects on high glucose (HG)-induced oxidative damage in RPE cells are not fully understood. In this study, we investigated the protective effect of paeoniflorin against HG-induced oxidative damage in cultured human RPE ARPE-19 cells, an in vitro model of hyperglycemia. Pretreatment with paeoniflorin markedly reduced HG-induced cytotoxicity and DNA damage. Paeoniflorin inhibited HG-induced apoptosis by suppressing activation of the caspase cascade, and this suppression was associated with the blockade of cytochrome c release to cytoplasm by maintaining mitochondrial membrane stability. In addition, paeoniflorin suppressed the HG-induced production of reactive oxygen species (ROS), increased the phosphorylation of nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox regulator, and the expression of its downstream factor heme oxygenase-1 (HO-1). On the other hand, zinc protoporphyrin (ZnPP), an inhibitor of HO-1, abolished the protective effect of paeoniflorin against ROS production in HG-treated cells. Furthermore, ZnPP reversed the protective effects of paeoniflorin against HG-induced cellular damage and induced mitochondrial damage, DNA injury, and apoptosis in paeoniflorin-treated cells. These results suggest that paeoniflorin protects RPE cells from HG-mediated oxidative stress-induced cytotoxicity by activating Nrf2/HO-1 signaling and highlight the potential therapeutic use of paeoniflorin to improve the symptoms of DR.

IGF2BPs-regulated TIN2 confers the malignant biological behaviors of gastric cancer cells.

The pathology of cardiovascular aging is complex, involving mitochondrial dysfunction, oxidative and nitrative stress, oxidative DNA injury, impaired lipid metabolism, cell death, senescence, and chronic inflammation. These processes lead to remodeling and structural changes in the cardiovascular system, resulting in a progressive decline in cardiovascular reserve capacity and health, and an increased risk of diseases and mortality. Excessive alcohol consumption exacerbates these risks by promoting hypertension, stroke, arrhythmias, coronary artery disease, cardiomyopathy, and sudden cardiac death, yet the effects of chronic alcohol consumption on cardiovascular aging remain unclear. Herein, we explored the impact of a 6-month 5% Lieber-DeCarli alcohol diet in young (3 months old) and aging (24–26 months old) Fisher F344BNF1 rats. We assessed detailed hemodynamics, mitochondrial function, oxidative/nitrative stress, lipid metabolism, inflammation, cell death, senescence, and myocardial fibrosis using the pressure–volume system, isolated vascular rings, and various histological, biochemical, and molecular biology methods. Alcohol consumption in both young and aging rats impaired mitochondrial function, disrupted cholesterol and triglyceride metabolism, and increased oxidative/nitrative stress, inflammation, cell death, and senescence, leading to a decline in systolic contractile function. In aging rats, alcohol further exacerbated diastolic dysfunction and myocardial fibrosis. Alcohol also increased oxidative/nitrative stress, apoptosis, and senescence in the vasculature, contributing to endothelial dysfunction and increased total peripheral resistance. Additionally, alcohol exacerbated the aging-related ventriculo-arterial uncoupling and diminished cardiac efficiency, further reducing cardiovascular reserve capacity. In conclusion, chronic alcohol consumption promotes cardiovascular aging and further diminishes the already impaired cardiac and vascular reserve capacity associated with aging.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11357-025-01613-w.