Mutation research. Genetic toxicology and environmental mutagenesis最新文献_第3页

Frequency of γ-H2AX foci, micronucleus formation, and radiation dose to the blood lymphocytes in pediatric and adult participants underwent computed tomography imaging 对儿童和成人参与者的γ-H2AX病灶频率、微核形成和对血液淋巴细胞的辐射剂量进行计算机断层成像

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-18 DOI: 10.1016/j.mrgentox.2025.503897

Divya K. Mohan , Nandhini K. , Aishwarya S. , Senthil Kumar M. , Swetha K. , Akshaya J. , Sudha Pattan , Venkata Sai P.M. , Venkateswarlu Raavi , Venkatachalam Perumal

Computed tomography (CT) is a widely used diagnostic imaging modality that contributes significantly to human healthcare. Despite the advantage, its extensive use increased concerns due to receiving radiation doses to pediatric patient's over adults during CT imaging. We evaluated the biological effects (Gamma-H2AX (γ-H2AX) foci and micronucleus (MN) formation) of low-dose X-radiation on the peripheral blood lymphocytes of pediatric (n = 45) and adult (n = 38) participants before and after CT imaging. Participant-specific organ doses were calculated using VirtualDose™CT software, weighted to the corresponding organ's blood volume, summed to derive the blood dose, and then related to induced DNA damage. A significant (p < 0.001) increase in γ-H2AX foci and MN frequencies was observed in both pediatric and adult groups after CT imaging. While the mean effective dose (ED) in pediatric and adult (16.21 ± 11.33 mSv and 31.30 ± 16.25 mSv) participants were significantly different (p < 0.001), the mean blood doses did not differ (9.83 ± 6.34 mGy and 12.82 ± 5.96 mGy) (p > 0.05), respectively. A weak correlation was observed between the induced DNA damage to that of ED and blood dose. The results suggest that damage to blood lymphocytes after CT imaging was observed by an increased γ-H2AX foci result of DNA double-strand breaks. The increase in MN frequency suggests activation of DNA repair, thereby contributing to minimal damage, although they are unstable. Therefore, it is necessary to follow up on the pediatric participants to look for stable aberrations to better relate DNA damage to exposure and long-term health effects, if any.

计算机断层扫描（CT）是一种广泛使用的诊断成像方式，对人类医疗保健有重要贡献。尽管有优势，但由于在CT成像时儿科患者接受的辐射剂量高于成人，因此其广泛使用增加了人们的担忧。我们评估了低剂量x射线对儿童（n = 45）和成人（n = 38）受试者外周血淋巴细胞的生物学效应（γ-H2AX （γ-H2AX）病灶和微核（MN）形成）。使用VirtualDose™CT软件计算参与者特定器官剂量，加权到相应器官的血容量，求和得出血剂量，然后与诱导的DNA损伤相关。在CT成像后，儿童组和成人组的γ-H2AX病灶和MN频率显著增加（p <； 0.001）。平均有效剂量(ED)在小儿和成人(16.21 ± 11.33毫西弗和31.30 ± 16.25 mSv)参与者明显不同(p & lt; 0.001),平均血剂量没有差别(9.83 ±6.34   mGy和12.82±5.96  mGy) (p 祝辞 0.05),分别。ED诱导的DNA损伤与血药剂量之间存在较弱的相关性。结果表明，DNA双链断裂的γ-H2AX灶增高是CT显像后淋巴细胞损伤的主要表现。MN频率的增加表明DNA修复的激活，从而导致最小的损伤，尽管它们是不稳定的。因此，有必要对儿童参与者进行随访，寻找稳定的畸变，以便更好地将DNA损伤与暴露和长期健康影响（如果有的话）联系起来。

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引用次数: 0

DNA damage and nuclear anomalies in peripheral blood lymphocytes from asthma patients and obese individuals 哮喘患者和肥胖者外周血淋巴细胞DNA损伤和核异常

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-12 DOI: 10.1016/j.mrgentox.2025.503889

Aswathi Pootheri , Medha Nagaraj , Nethra Raghuraman , Sohini Dey , Swathi R , Sombodhi Bhattacharya , Yeshi Yangchen , S. Santoshi Iyer , Mohnish Ram G , Narmada Ashok , Wilner Martinez Lopez , Radha Saraswathy

Asthma is a chronic, non-communicable respiratory disorder affecting approximately 262 million people worldwide, with India projected to become one of the leading countries in prevalence. Asthma is well-established as a condition of chronic inflammation of the airways and related to systemic oxidative stress, but relatively not much is known about the genomic instability associated with asthma. On the other hand, obesity is found in 650 million people worldwide and 113 million people in India. Studies reported links between asthma and obesity, which include adipose tissue dysfunction and inefficient blood monocyte efferocytosis. Obesity enhances reactive oxygen species (ROS) production and inflammation, leading to DNA lesions. Thus, the aim of this study was to assess the DNA damage and frequencies of micronuclei (MNi), nucleoplasmic bridges (NPB), and nuclear buds (NBUD) in the lymphocytes of asthma patients and obese individuals. This study evaluates the DNA damage and nuclear anomalies in (n = 435) subjects (asthma patients n = 100, asthmatic obese patients n = 131, obese n = 100 and controls n = 104). An alkaline comet assay was used to assess DNA damage and nuclear anomalies were assessed by cytokinesis block micronucleus cytome (CBMN-Cyt) assay. All subjects were recruited between the age of 20 and 60 years. The total DNA damage, MNi, and frequency of total nuclear anomalies were found to be significantly higher in asthma male and female patients, asthmatic obese male and female patients, and obese males and females in comparison to control males and females (p < 0.05). The total comet score showed a positive correlation with the frequency of total nuclear anomalies in asthma male and female patients and obese males, respectively. Overall the findings demonstrate that inflammation and oxidative stress in asthma and obesity lead to DNA damage and genomic instability.

哮喘是一种慢性非传染性呼吸系统疾病，影响全球约2.62亿人，印度预计将成为患病率最高的国家之一。众所周知，哮喘是一种气道慢性炎症，与全身氧化应激有关，但相对而言，人们对哮喘相关的基因组不稳定性知之甚少。另一方面，全球有6.5亿人肥胖，印度有1.13亿人肥胖。研究报告了哮喘和肥胖之间的联系，包括脂肪组织功能障碍和低效率的血液单核细胞efferocytosis。肥胖增加活性氧（ROS）的产生和炎症，导致DNA损伤。因此，本研究的目的是评估哮喘患者和肥胖者淋巴细胞中微核（MNi）、核质桥（NPB）和核芽（NBUD）的DNA损伤和频率。本研究评估的DNA损伤和核异常(n = 435)科目(哮喘患者n = 100,哮喘肥胖病人n = 131,肥胖n = 100和控制 = 104)。用碱性彗星法评估DNA损伤，用细胞分裂阻断微核细胞组（cmbn - cyt）法评估核异常。所有受试者的年龄都在20至60岁之间。哮喘男女患者、哮喘肥胖男女患者、肥胖男女患者的总DNA损伤、MNi、总核异常频率均明显高于对照组（p <； 0.05）。在哮喘男女患者和肥胖男性患者中，彗核总得分分别与总核异常频率呈正相关。总的来说，研究结果表明哮喘和肥胖中的炎症和氧化应激会导致DNA损伤和基因组不稳定。

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引用次数: 0

Cellular uptake, induction of reactive oxygen species, and genotoxicity of differently sized cobalt oxide nanoparticles in human peripheral blood mononuclear cells in vitro 细胞摄取，诱导活性氧，不同大小的钴氧化物纳米颗粒在体外人外周血单核细胞的遗传毒性

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-10 DOI: 10.1016/j.mrgentox.2025.503888

Milda Babonaitė, Veronika Dedonytė, Emilija Striogaitė, Juozas R. Lazutka

Cobalt (II, III) oxide nanoparticles (Co₃O₄-NPs) have potential applications in different technological and medical fields, including drug delivery and as novel anticancer treatments. However, widespread application could lead to a high-level direct human exposure, raising concerns about their genotoxic potential. This study aimed to evaluate the cytotoxicity and genotoxicity of Co₃O₄-NPs in human peripheral blood mononuclear cells (PBMCs) in vitro. Two sizes of Co₃O₄-NPs (10–30 nm and < 50 nm) were tested to understand any size-dependent differences in genotoxicity. The study measured NP uptake, reactive oxygen species (ROS) generation, cell viability, DNA strand breaks, micronuclei formation, and sister chromatid exchange to assess the cyto-genotoxic potential of Co₃O₄-NPs. Flow cytometric analysis revealed that Co₃O₄-NPs with a primary size of < 50 nm were more efficiently internalized by human PBMCs and induced higher ROS levels than 10–30 nm particles. Both nanoparticles’ sizes induced significant primary DNA damage at non-cytotoxic concentrations, often in a dose-dependent manner. Cytogenetic analysis demonstrated that Co₃O₄-NPs exert genotoxic effects, with < 50 nm NPs inducing more significant DNA damage and reduced cell viability than smaller nanoparticles. Additionally, interindividual differences in response to exposure to Co₃O₄–NPs were observed. The study findings suggest that Co₃O₄-NPs possess genotoxic potential in human PBMCs in vitro, raising safety concerns about their use. This highlights the need for comprehensive genotoxicity assessments of Co₃O₄-NPs in different cell types.

钴（II， III）氧化物纳米颗粒（Co3O4-NPs）在不同的技术和医疗领域具有潜在的应用，包括药物输送和新型抗癌治疗。然而，广泛应用可能导致高水平的人类直接暴露，引起人们对其遗传毒性潜在的担忧。本研究旨在评价Co3O4-NPs对人外周血单核细胞（PBMCs）的细胞毒性和遗传毒性。测试了两种尺寸的Co3O4-NPs(10-30 nm和<； 50 nm)，以了解遗传毒性的任何尺寸依赖性差异。该研究测量了NP摄取、活性氧（ROS）产生、细胞活力、DNA链断裂、微核形成和姐妹染色单体交换，以评估Co3O4-NPs的细胞遗传毒性潜力。流式细胞分析显示，初始尺寸为<； 50 nm的Co3O4-NPs比10-30 nm的颗粒更有效地被人pbmc内化，并诱导更高的ROS水平。在非细胞毒性浓度下，这两种纳米颗粒的大小通常以剂量依赖的方式诱导了显著的原发性DNA损伤。细胞遗传学分析表明，Co3O4-NPs具有遗传毒性作用，<； 50 nm NPs比更小的纳米颗粒诱导更明显的DNA损伤和细胞活力降低。此外，还观察了暴露于Co3O4-NPs的个体间差异。研究结果表明，Co3O4-NPs在体外对人pbmc具有遗传毒性，引起了对其使用安全性的担忧。这突出了对不同细胞类型的Co3O4-NPs进行综合遗传毒性评估的必要性。

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引用次数: 0

Protective role of Cockayne Syndrome B (CSB) protein in maintaining genome integrity in human cells under oxidative stress Cockayne综合征B （CSB）蛋白在氧化应激下维持人类细胞基因组完整性中的保护作用

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-09 DOI: 10.1016/j.mrgentox.2025.503887

Grace Kah Mun Low, Gavin Yong-Quan Ng, Dimphy Zeegers, Aloysius Ting, Kalpana Gopalakrishnan, Aik Kia Khaw, Manikandan Jayapal, Manoor Prakash Hande

Cockayne Syndrome (CS), a progeroid disorder characterised by premature ageing and neurodevelopmental abnormalities, is primarily caused by mutations in the CSB protein, a key component of the transcription-coupled nucleotide excision repair pathway. This study investigates the role of CSB in managing oxidative DNA damage and preserving telomere integrity under oxidative stress. Using CSB-deficient human fibroblasts (CS-B) and matched controls, we exposed cells to acute and chronic oxidative stress via hydrogen peroxide (H₂O₂) and elevated oxygen (40 %) levels. CS-B fibroblasts showed relative resistance to acute oxidative stress in terms of cell death, maintaining viability and displaying limited cell cycle arrest. In contrast, chronic oxidative exposure induced accelerated senescence in CS-B cells, evidenced by increased telomere attrition, senescent morphology, and early activation of senescence-associated β-galactosidase associated with increased DNA damage and aberrant DNA repair. Gene expression profiling revealed downregulation of key DNA repair and cell cycle genes in CS-B fibroblasts following H₂O₂ treatment, indicating impaired damage response pathways. These findings highlight the essential role of CSB in genome maintenance and suggest that its loss contributes to CS pathology through heightened sensitivity to chronic oxidative stress and telomere dysfunction. This work enhances our understanding of CS-related cellular mechanisms and may inform future therapeutic strategies targeting oxidative stress and DNA repair.

柯凯因综合征（CS）是一种以早衰和神经发育异常为特征的类早衰疾病，主要由CSB蛋白突变引起，CSB蛋白是转录偶联核苷酸切除修复途径的关键成分。本研究探讨了CSB在氧化应激下管理氧化DNA损伤和保持端粒完整性中的作用。使用csb缺陷的人成纤维细胞（CS-B）和匹配的对照，我们通过过氧化氢（H₂O₂）和高氧（40 %）水平将细胞暴露于急性和慢性氧化应激中。CS-B成纤维细胞在细胞死亡、维持活力和有限的细胞周期阻滞方面显示出对急性氧化应激的相对抗性。相反，慢性氧化暴露诱导CS-B细胞加速衰老，这可以通过端粒磨损增加、衰老形态和衰老相关β-半乳糖苷酶的早期激活来证明，该酶与DNA损伤增加和异常DNA修复有关。基因表达谱显示，在h2o2处理后，CS-B成纤维细胞中关键的DNA修复和细胞周期基因下调，表明损伤反应途径受损。这些发现强调了CSB在基因组维持中的重要作用，并表明CSB的缺失通过对慢性氧化应激和端粒功能障碍的敏感性增加而导致CS病理。这项工作增强了我们对cs相关细胞机制的理解，并可能为未来针对氧化应激和DNA修复的治疗策略提供信息。

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引用次数: 0

Genotoxicity mode of action exploration of polyethylene glycol terephthalate (PET) acetic acid migration solution under repeated-dose exposure in rats 聚对苯二甲酸乙二醇酯（PET）醋酸迁移液对大鼠重复剂量暴露的遗传毒性作用模式探讨

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-09-09 DOI: 10.1016/j.mrgentox.2025.503886

Liang Wang , Li Cao , Xiaoya Wang , Yufei Liu , Weiwei Zhang , Yurui Gou , Jun He , Jiao Huo , Xiaomeng Li , Jinyao Chen

As a commonly used material that contacts food, polyethylene glycol terephthalate (PET) may interact with food, and since certain components can migrate, this has become a food safety concern. This study aims to investigate the genotoxicity of PET acetic acid migration solution and its toxic mode of action using an in vivo multi-endpoint genotoxicity evaluation system and quantitative liver proteomics analysis. Forty-eight male Sprague–Dawley rats were randomly divided into eight groups: the PET acetic acid migration solution group, the acetic acid group, the phosphate-buffered saline (PBS) control group, the N-ethyl-N-nitrosourea (ENU) positive control group, and their corresponding satellite groups. PBS and ENU were administered by gavage, while the PET acetic acid migration solution and acetic acid were administered orally in the drinking water. The exposure duration was 35 days, followed by a recovery period of 15 days. The PET acetic acid migration solution can cause heart, liver, and kidney injury in rats. On the 15th day, mutations were seen in the Pig-a gene test. On the 35th day, DNA damage was observed in peripheral blood and liver cells. Gene ontology (GO) analysis of the liver proteomics revealed enrichment in DNA metabolism and binding processes, while Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted the DNA replication pathway. Immunohistochemical analysis demonstrated a significant increase in 8-hydroxydeoxyguanosine (8-OHdG) and a decrease in single-stranded-binding (SSB) protein in the PET acetic acid migration solution group. In summary, the PET acetic acid migration solution has the potential to induce DNA damage, possibly by inhibiting DNA replication and DNA repair pathways. However, the likelihood of genetic toxicity is low.

聚乙二醇对苯二甲酸乙二醇酯（PET）作为一种常用的与食品接触的材料，可能与食品发生相互作用，并且由于某些成分可以迁移，这已经成为食品安全问题。本研究旨在通过体内多终点遗传毒性评价系统和定量肝脏蛋白质组学分析，探讨PET乙酸迁移液的遗传毒性及其毒性作用方式。48只雄性Sprague-Dawley大鼠随机分为8组：PET乙酸迁移液组、乙酸组、磷酸盐缓冲盐水（PBS）对照组、n -乙基-n -亚硝基脲（ENU）阳性对照组及相应的卫星组。PBS和ENU灌胃，PET醋酸迁移液和醋酸灌胃。暴露时间为35天，恢复期为15天。PET醋酸迁移液可引起大鼠心、肝、肾损伤。第15天，在猪-a基因测试中发现了突变。第35天，外周血和肝细胞均出现DNA损伤。肝脏蛋白质组学的基因本体（GO）分析揭示了DNA代谢和结合过程的富集，而京都基因与基因组百科全书（KEGG）分析则强调了DNA复制途径。免疫组织化学分析显示，PET醋酸迁移液组8-羟基脱氧鸟苷（8-OHdG）显著增加，单链结合（SSB）蛋白显著减少。综上所述，PET乙酸迁移液可能通过抑制DNA复制和DNA修复途径诱导DNA损伤。然而，遗传毒性的可能性很低。

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引用次数: 0

Protective effects of nicotinamide mononucleotide on DNA damage and cell death in A549 cells and aging in C. elegans caused by hydrogen peroxide 烟酰胺单核苷酸对过氧化氢致秀丽隐杆线虫A549细胞DNA损伤、细胞死亡及衰老的保护作用

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-30 DOI: 10.1016/j.mrgentox.2025.503885

Chuncao He , Xueying Sun , Ting Xu , Xiaoqiang Hu , Jinyi Han , Kexin Xu , Qin Song , Ting Duan , Jun Yang

Oxidative stress is a major factor for aging. Nicotinamide mononucleotide (NMN) is a naturally occurring bioactive nucleotide and a precursor for nicotinamide adenine dinucleotide (NAD⁺), and accumulating evidences have shown that NMN is a promising anti-aging agent, however, the underlying molecular mechanisms remain to be elucidated. Therefore, in the current study, the protective effects of NMN on oxidative stress-induced damage to cells, in particular, the various types of cell death induced by oxidative stress, were evaluated. It was found that NMN inhibited hydrogen peroxide (H₂O₂)-induced decrease in A549 cell viability·H₂O₂-triggered reactive oxygen species (ROS) production was also diminished by NMN. Furthermore, results from 8-hydoxy 2 deoxyguanosine (8-OHdG) level, alkaline comet assay, and γ-H2AX foci formation indicated that NMN protected cells from H₂O₂-induced DNA damage. Detailed cell death analysis revealed that H₂O₂ caused A549 cell death mainly through apoptosis and ferroptosis, but not necroptosis or parthanatos, and NMN could effectively inhibit the apoptosis and ferroptosis pathways, thus protected cells from H₂O₂-induced cell death. Finally, we validated NMN protected against H₂O₂-induced organismal senescence in C. elegans. Taken together, these results suggests that NMN is a potent agent against oxidative stress, which could contribute to its anti-aging effects.

氧化应激是衰老的主要因素。烟酰胺单核苷酸（NMN）是一种天然存在的生物活性核苷酸，是烟酰胺腺嘌呤二核苷酸（NAD+）的前体，越来越多的证据表明NMN是一种很有前景的抗衰老剂，但其潜在的分子机制仍有待阐明。因此，在本研究中，我们评估了NMN对氧化应激诱导的细胞损伤，特别是氧化应激诱导的各种类型的细胞死亡的保护作用。研究发现，NMN抑制过氧化氢（H2O2）诱导的A549细胞活力下降，NMN也减少H2O2引发的活性氧（ROS）的产生。此外，8-羟基2脱氧鸟苷（8-OHdG）水平、碱性彗星试验和γ-H2AX灶形成的结果表明，NMN可以保护细胞免受h2o2诱导的DNA损伤。详细的细胞死亡分析表明，H2O2主要通过凋亡和ferroptosis导致A549细胞死亡，而不是通过坏死性死亡或旁咽下，NMN可以有效抑制凋亡和ferroptosis途径，从而保护细胞免受H2O2诱导的细胞死亡。最后，我们验证了NMN对h2o2诱导的秀丽隐杆线虫的机体衰老具有保护作用。综上所述，这些结果表明NMN是一种有效的抗氧化应激剂，这可能有助于其抗衰老作用。

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引用次数: 0

Perchloroethylene: Genotoxicity and cytotoxicity in human peripheral blood lymphocytes in vitro 过氯乙烯：体外对人外周血淋巴细胞的遗传毒性和细胞毒性

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-26 DOI: 10.1016/j.mrgentox.2025.503884

Tülay Aşkın Çelik , Ümit Ünsal

Perchloroethylene (PCE), a widely used solvent, is classified as a probable human carcinogen. We have studied its genotoxicity, clastogenicity, and cytotoxicity in cultured human peripheral lymphocytes (HPLs). Cytogenetic tests used were the chromosomal aberration (CA), sister chromatid exchange (SCE), mitotic index (MI), replication index (RI), and micronucleus (MN) assays. Positive results were obtained with each of these assays: a dose-dependent increase in CA, a significant increase in SCE, a significant decrease in MI and RI, and an increase in MN frequency at the highest concentration of PCE. These results demonstrate that PCE induces significant genotoxic and clastogenic effects in human peripheral lymphocytes.

全氯乙烯（PCE）是一种广泛使用的溶剂，被列为可能的人类致癌物。我们研究了其在培养的人外周血淋巴细胞（HPLs）中的遗传毒性、致裂性和细胞毒性。使用的细胞遗传学检测包括染色体畸变（CA）、姐妹染色单体交换（SCE）、有丝分裂指数（MI）、复制指数（RI）和微核（MN）测定。这些实验均获得阳性结果：CA呈剂量依赖性增加，SCE显著增加，MI和RI显著降低，在PCE浓度最高时MN频率增加。这些结果表明，PCE对人外周血淋巴细胞具有显著的遗传毒性和致裂作用。

引用次数: 0

The PPAR-β/δ agonist GW0742 alleviates DNA damage and lupus nephritis in an animal model of systemic lupus erythematosus via restoring DNA repair gene expression PPAR-β/δ激动剂GW0742通过恢复DNA修复基因表达，减轻系统性红斑狼疮动物模型的DNA损伤和狼疮肾炎

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-01 DOI: 10.1016/j.mrgentox.2025.503881

Mohamed S.M. Attia , Mohammed A. Al-Hamamah , Sheikh F. Ahmad , Ahmed Nadeem , Saleh A. Bakheet , Mushtaq A. Ansari , Gamaleldin I. Harisa , Talha Bin Emran , Sabry M. Attia

Systemic lupus erythematosus (SLE) is a persistent autoimmune inflammatory disease associated with an elevated risk of kidney damage. The etiology of SLE remains unclear; nevertheless, current investigations increasingly indicate that increased DNA damage and deficiencies in the mechanisms of its repair might contribute to its pathogenesis, necessitating the identification and management of the disease. Therapies for SLE have improved considerably over recent decades. However, drugs that specifically address the underlying pathogenic pathways, such as potential DNA repair deficiencies, are unavailable. In this situation, drugs that ameliorate the altered DNA damage/repair might be a possible option for treating SLE. We investigated whether GW0742, an agonist of the peroxisome proliferator activator receptor β/δ, improves kidney function and ameliorates DNA damage/repair alteration in female lupus-prone mice. The results demonstrate that the repeated administration of GW0742 significantly ameliorates DNA damage/repair alteration in the bone marrow cells of lupus-prone animals, as assessed by the comet test. Furthermore, the administration of GW0742 restored the impaired DNA damage/repair pathway in lupus-prone mice by decreasing Gadd45a and p53 expression while elevating Ogg1 and Parp1 in the kidney tissues. The administration of GW0742 recovered the disturbed kidney redox balance in lupus-prone mice. It also ameliorated the altered biochemical markers related to lupus nephritis, as demonstrated by reduced levels of urinary protein and albumin, serum creatinine, and BUN. GW0742's protective outcome was verified by its ability to diminish the increased inflammatory marker MPO activity and ameliorated kidney histological characteristics of SLE. This suggests that GW0742 is a promising novel therapeutic agent for managing SLE and its associated complications.

系统性红斑狼疮（SLE）是一种持续性自身免疫性炎症性疾病，与肾损害风险升高相关。SLE的病因尚不清楚；然而，目前的研究越来越多地表明，DNA损伤的增加及其修复机制的缺陷可能导致其发病机制，因此有必要对该疾病进行识别和管理。近几十年来，SLE的治疗方法有了很大的改进。然而，专门针对潜在致病途径的药物，如潜在的DNA修复缺陷，是不可用的。在这种情况下，改善DNA损伤/修复改变的药物可能是治疗SLE的一种可能选择。我们研究了GW0742，一种过氧化物酶体增殖物激活物受体β/δ的激动剂，是否能改善雌性狼疮易感小鼠的肾功能和改善DNA损伤/修复改变。结果表明，重复给药GW0742显著改善狼疮易感动物骨髓细胞的DNA损伤/修复改变，如彗星试验所评估的那样。此外，GW0742通过降低Gadd45a和p53的表达，同时提高肾组织中Ogg1和Parp1的表达，恢复了狼疮易感小鼠受损的DNA损伤/修复途径。GW0742可恢复狼疮易感小鼠的肾脏氧化还原平衡。它还改善了与狼疮肾炎相关的生化标志物的改变，如尿蛋白和白蛋白、血清肌酐和BUN水平的降低。GW0742的保护效果通过其降低炎症标志物MPO活性和改善SLE肾脏组织学特征的能力得到证实。这表明GW0742是一种很有前景的治疗SLE及其相关并发症的新型药物。

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引用次数: 0

Effect of xthA deletion in the activation of the E. coli SOS response by gamma rays, UV-C light and other genotoxic agents xthA缺失对γ射线、UV-C光和其他基因毒性物质激活大肠杆菌SOS反应的影响

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-01 DOI: 10.1016/j.mrgentox.2025.503879

Jorge Serment-Guerrero , Viridiana Dominguez-Monroy , Martha Patricia Cruces-Martinez , Jorge Luis Fuentes-Lorenzo , Silvia Cristina Serment-Gonzalez

The SOS response contains a set of about 45 genes related to the repair or tolerance to DNA damage. These genes are normally blocked but when lesions upon the genetic material occur an SOS signal is generated allowing their expression. Most types of DNA lesions must be modified or processed to induce SOS. In a previous work, a model was proposed suggesting the possible paths that could be followed from the different types of lesions to the induction of the response. One of these possible routes is through the base excision repair mechanism (BER). Since in E. coli the AP endonuclease exonuclease III plays a key role in this repair pathway, in the present study we evaluate the participation of xthA product in the processing of DNA lesions made by gamma rays, UV-C light, ethyl methanesulphonate, methyl methanesulphonate, mitomycin C, hydrogen peroxide and tert-buthylhydroperoxide to trigger the SOS response. A strain defective in xthA and a wt strain were exposed to different genotoxic agents and survival and SOS induction were analyzed. The results show differences in the survival and SOS induction to each genotoxic agent between the wt strain and the xthA mutant; depending on the type of DNA damage inflicted, the SOS response level was either higher or lower compared to the wt strain. This suggests that while the AP endonuclease role of exonuclease III enzyme suppresses SOS induction when bulky and methylated lesions occur, it enhances SOS induction when the damage is generated by ROS, in agreement with a previously proposed model.

SOS反应包含一组约45个基因，这些基因与DNA损伤的修复或耐受有关。这些基因通常是被阻断的，但当遗传物质发生病变时，就会产生SOS信号，允许它们表达。大多数类型的DNA损伤必须经过修饰或处理才能诱发SOS。在之前的工作中，提出了一个模型，提出了从不同类型的病变到诱导反应的可能路径。其中一个可能的途径是通过碱基切除修复机制（BER）。由于在大肠杆菌中，AP核酸内切酶外切酶III在这一修复途径中起着关键作用，因此在本研究中，我们评估了xthA产物在伽马射线、UV-C光、甲磺酸乙酯、甲磺酸甲酯、丝裂霉素C、过氧化氢和过氧化叔丁基氢引起的DNA损伤的处理中参与SOS反应。将一株xthA缺陷菌株和一株wt菌株暴露于不同的基因毒性物质中，分析其存活和SOS诱导情况。结果表明，wt菌株和xthA突变体的存活率和对各基因毒性物质的SOS诱导存在差异；根据DNA损伤类型的不同，与wt菌株相比，SOS反应水平或高或低。这表明，虽然外切酶III酶的AP内切酶作用在大体积和甲基化病变发生时抑制SOS诱导，但当ROS产生损伤时，它会增强SOS诱导，这与先前提出的模型一致。

{"title":"Effect of xthA deletion in the activation of the E. coli SOS response by gamma rays, UV-C light and other genotoxic agents","authors":"Jorge Serment-Guerrero , Viridiana Dominguez-Monroy , Martha Patricia Cruces-Martinez , Jorge Luis Fuentes-Lorenzo , Silvia Cristina Serment-Gonzalez","doi":"10.1016/j.mrgentox.2025.503879","DOIUrl":"10.1016/j.mrgentox.2025.503879","url":null,"abstract":"<div><div>The SOS response contains a set of about 45 genes related to the repair or tolerance to DNA damage. These genes are normally blocked but when lesions upon the genetic material occur an SOS signal is generated allowing their expression. Most types of DNA lesions must be modified or processed to induce SOS. In a previous work, a model was proposed suggesting the possible paths that could be followed from the different types of lesions to the induction of the response. One of these possible routes is through the base excision repair mechanism (BER). Since in <em>E. coli</em> the AP endonuclease exonuclease III plays a key role in this repair pathway, in the present study we evaluate the participation of <em>xthA</em> product in the processing of DNA lesions made by gamma rays, UV-C light, ethyl methanesulphonate, methyl methanesulphonate, mitomycin C, hydrogen peroxide and tert-buthylhydroperoxide to trigger the SOS response. A strain defective in <em>xthA</em> and a <em>wt</em> strain were exposed to different genotoxic agents and survival and SOS induction were analyzed. The results show differences in the survival and SOS induction to each genotoxic agent between the <em>wt</em> strain and the <em>xthA</em> mutant; depending on the type of DNA damage inflicted, the SOS response level was either higher or lower compared to the <em>wt</em> strain. This suggests that while the AP endonuclease role of exonuclease III enzyme suppresses SOS induction when bulky and methylated lesions occur, it enhances SOS induction when the damage is generated by ROS, in agreement with a previously proposed model.</div></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":"906 ","pages":"Article 503879"},"PeriodicalIF":2.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144779938","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Epistatic interactions in DNA repair genes as biomarkers of susceptibility for DNA damage in pesticide-exposed agricultural workers of Punjab, North-West India DNA修复基因的上位相互作用作为农药暴露农业工人DNA损伤易感性的生物标志物

IF 2.5 4区医学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY

Mutation research. Genetic toxicology and environmental mutagenesis

Pub Date : 2025-08-01 DOI: 10.1016/j.mrgentox.2025.503880

Karashdeep Kaur , Rupinder Kaur

Some occupational exposures to pesticides have been associated with genotoxicity which arises from DNA single-strand breaks (SSBs), repair of DNA double-strand breaks (DSBs), DNA adduct formation, or DNA-DNA and DNA-protein cross-links. Polymorphisms in genes encoding enzymes of DNA repair pathways may modulate the individual’s susceptibility to pesticide-induced genotoxicity. A total of 450 subjects were included in this study, which comprises 225 agricultural workers exposed to complex mixtures of pesticides and 225 non-exposed controls from Punjab, North-West India. Susceptibility of OGG1 Ser326Cys (C1245G), XRCC1 Arg194Trp (C26304T), XRCC1 Arg399Gln (G28152A), XPC Lys939Gln (A2920C), XPC Ala499Val (C21151T), XPD Asp312Asn (G23591A), XPD Lys715Gln (A35931C), XPF Arg415Gln (G1244A), XPG Asp1104His (G3507C), ERCC1 3′-UTR (C8092A) and ERCC1 Asn118Asn (C354T) gene polymorphisms with pesticide-induced DNA damage was determined by Kruskal-Wallis test. The association of epistatic gene interactions with DNA damage was studied by ANOVA. The results indicated significant interactions of variant OGG1 326Ser/Cys genotype with XRCC1 194Arg/Trp and XRCC1 399Arg/Gln genotypes in increased susceptibility to DNA damage. XPC 939Gln/Gln genotype significantly interacts with XPC 499Ala/Val, XPD 312Asp/Asp and XPD 715Gln/Gln variant genotypes to increase DNA damage susceptibility. Among exposed XPF 415Gln/Gln individuals, DNA damage was significantly higher in those individuals who had variant XPG Asp/His and ERCC1 8092CA genotypes. We observed some statistically significant epistatic gene interactions in DNA repair pathways in modulating DNA damage, which may be used as biomarkers of susceptibility in pesticide-exposed agricultural workers of Punjab, North-West India.

一些职业性农药暴露与DNA单链断裂（SSBs）、DNA双链断裂（DSBs）修复、DNA加合物形成或DNA-DNA和DNA-蛋白质交联引起的遗传毒性有关。编码DNA修复途径酶的基因多态性可能调节个体对农药遗传毒性的易感性。本研究共纳入450名受试者，其中包括225名接触复杂农药混合物的农业工人和225名来自印度西北部旁遮普省的非接触对照者。采用Kruskal-Wallis试验检测OGG1 Ser326Cys （C1245G）、XRCC1 Arg194Trp （C26304T）、XRCC1 Arg399Gln （G28152A）、XPC Lys939Gln （A2920C）、XPC Ala499Val （C21151T）、XPD Asp312Asn （G23591A）、XPD Lys715Gln （A35931C）、XPF Arg415Gln （G1244A）、XPG Asp1104His （G3507C）、ERCC1 Asn118Asn （C354T）基因多态性与农药诱导DNA损伤的易感性。通过方差分析研究上位性基因相互作用与DNA损伤的关系。结果表明，变异OGG1 326Ser/Cys基因型与XRCC1 194Arg/Trp和XRCC1 399Arg/Gln基因型的交互作用显著增加了DNA损伤的易感性。XPC 939Gln/Gln基因型与XPC 499Ala/Val、XPD 312Asp/Asp和XPD 715Gln/Gln基因型显著相互作用，增加DNA损伤易感性。在暴露的XPF 415Gln/Gln个体中，变异XPG Asp/His和ERCC1 8092CA基因型个体的DNA损伤显著更高。我们观察到在DNA修复途径中调节DNA损伤的一些具有统计学意义的epistatic基因相互作用，这可能被用作印度西北部旁遮普省农药暴露农业工人的易感性生物标志物。

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引用次数: 0