Pub Date : 2025-07-01Epub Date: 2025-08-07DOI: 10.1016/j.mrrev.2025.108558
Leigh Donnellan, Michael Fenech, Varinderpal S Dhillon, Clifford Young, Peter Hoffmann, Permal Deo
Methylglyoxal (MGO) is a highly reactive metabolite formed from glycolysis that can form advanced glycation endproducts (AGEs) on proteins and DNA. It has been well established that MGO induces DNA double strand breaks as a result of modifications on deoxyguanosine residues. However, recent studies shed new light on the genotoxic properties of MGO by its ability to cause chromosomal mis-segregation events, and other forms of chromosomal instability. These outcomes open a new avenue in which protein modifications, rather than DNA modifications, result in DNA damage. Herein, we present several hypotheses on how modification of proteins by MGO might cause these chromosome mis-segregation events based on identified protein modification sites from proteomic studies. These include various cell cycle proteins, such as those involved in sister chromatid cohesion, centrosome formation and histone proteins. Overall, recent studies implicate MGO in whole chromosome loss events, amongst other chromosomal instability events, suggesting it as a key player in cancer development and progression.
{"title":"Role of methylglyoxal protein modifications in DNA damage and chromosomal instability: Emerging molecular mechanisms.","authors":"Leigh Donnellan, Michael Fenech, Varinderpal S Dhillon, Clifford Young, Peter Hoffmann, Permal Deo","doi":"10.1016/j.mrrev.2025.108558","DOIUrl":"10.1016/j.mrrev.2025.108558","url":null,"abstract":"<p><p>Methylglyoxal (MGO) is a highly reactive metabolite formed from glycolysis that can form advanced glycation endproducts (AGEs) on proteins and DNA. It has been well established that MGO induces DNA double strand breaks as a result of modifications on deoxyguanosine residues. However, recent studies shed new light on the genotoxic properties of MGO by its ability to cause chromosomal mis-segregation events, and other forms of chromosomal instability. These outcomes open a new avenue in which protein modifications, rather than DNA modifications, result in DNA damage. Herein, we present several hypotheses on how modification of proteins by MGO might cause these chromosome mis-segregation events based on identified protein modification sites from proteomic studies. These include various cell cycle proteins, such as those involved in sister chromatid cohesion, centrosome formation and histone proteins. Overall, recent studies implicate MGO in whole chromosome loss events, amongst other chromosomal instability events, suggesting it as a key player in cancer development and progression.</p>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"108558"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108566
Peter Møller , Goran Gajski , Marko Gerić , Lisa Giovannelli , Amaya Azqueta , Anja Haveric , Helga Stopper , Ezgi Eyluel Bankoglu , Andrew Collins , Carina Ladeira
The comet assay is widely used in human biomonitoring studies of environmental and occupational exposures. However, it is clear from multiple studies that various types of confounding factors might affect the direct relationship between exposure and DNA damage in the comet assay. In addition to common confounders such as age, sex, and smoking, other factors considered to be important determinants for background levels of DNA damage in the comet assay include exhaustive physical exercise, chronic diseases, medical treatment, and diet. These are typically controlled in biomonitoring studies by restriction or matching of subjects. Period effects (or seasonal variation) have been observed in a relatively large number of studies. There are various putative factors, which may cause period effects, including temporal variation in solar radiation, temperature, and air pollution. The present review describes the effects of these confounding factors in measurements of DNA strand breaks by the comet assay. In general, the literature does not indicate that any confounding factor is consistently associated with an increased level of DNA damage, measured by the comet assay. In this respect, it is important to balance the need to control for confounding with the risk of introducing in the statistical analysis a variable, which is influenced by exposure and outcome (i.e. collider bias). In addition, it is important that investigators describe procedures for controlling the effect of confounding factors in the selection of subjects and statistical analysis. Care should be taken in study design and statistical analysis to avoid unwanted effects of confounding factors.
{"title":"The comet assay as a tool in human biomonitoring studies: Effects of confounding factors","authors":"Peter Møller , Goran Gajski , Marko Gerić , Lisa Giovannelli , Amaya Azqueta , Anja Haveric , Helga Stopper , Ezgi Eyluel Bankoglu , Andrew Collins , Carina Ladeira","doi":"10.1016/j.mrrev.2025.108566","DOIUrl":"10.1016/j.mrrev.2025.108566","url":null,"abstract":"<div><div>The comet assay is widely used in human biomonitoring studies of environmental and occupational exposures. However, it is clear from multiple studies that various types of confounding factors might affect the direct relationship between exposure and DNA damage in the comet assay. In addition to common confounders such as age, sex, and smoking, other factors considered to be important determinants for background levels of DNA damage in the comet assay include exhaustive physical exercise, chronic diseases, medical treatment, and diet. These are typically controlled in biomonitoring studies by restriction or matching of subjects. Period effects (or seasonal variation) have been observed in a relatively large number of studies. There are various putative factors, which may cause period effects, including temporal variation in solar radiation, temperature, and air pollution. The present review describes the effects of these confounding factors in measurements of DNA strand breaks by the comet assay. In general, the literature does not indicate that any confounding factor is consistently associated with an increased level of DNA damage, measured by the comet assay. In this respect, it is important to balance the need to control for confounding with the risk of introducing in the statistical analysis a variable, which is influenced by exposure and outcome (i.e. collider bias). In addition, it is important that investigators describe procedures for controlling the effect of confounding factors in the selection of subjects and statistical analysis. Care should be taken in study design and statistical analysis to avoid unwanted effects of confounding factors.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108566"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108567
Peter Møller , Ezgi Eyluel Bankoglu , Helga Stopper , Goran Gajski , Marko Gerić , Anja Haveric , Amaya Azqueta , Lisa Giovannelli , Andrew Collins , Carina Ladeira
Exposure to heavy metals such as lead, arsenic and chromium is associated with genotoxicity and increased risk of cancer. In this systematic review and meta-analysis, we have assessed effects of heavy metal exposure on levels of DNA strand breaks in leukocytes, measured by the comet assay, in human biomonitoring studies. We distinguish between traditional toxic metals (lead), semi-metals/metalloids (arsenic), transition metals (chromium), and other heavy metals. The literature search led to 66 studies, which were assessed by meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to lead (1.99, 95 % CI: 1.47, 2.51), arsenic (1.36, 95 % CI: 0.94, 1.77), chromium/welding fume (2.03, 95 % CI: 1.48, 2.57), and other heavy metals (0.81, 95 % CI: 0.45, 1.18). Subgroup analysis indicates that all studies combined from middle-income countries have higher effect size (1.99, 95 % CI: 1.63, 2.35) than have studies from high-income countries (0.81, 95 % CI: 0.37, 1.26). The lower effect size in high-income countries may be due to differences in exposure levels, related to stricter regulation of emissions or more awareness/use of personal protective equipment in the working environment. Sensitivity analysis does not unequivocally link effect size to comet assay measurement bias, inferred by insufficient information on comet assay procedures, missing assay controls, non-blinded analysis of samples, or exposure misclassification. In conclusion, this systematic review and meta-analysis shows that exposure to heavy metals - lead, arsenic and chromium – is associated with increased levels of DNA strand breaks in human leukocytes.
{"title":"The comet assay as a tool in human biomonitoring of exposure to heavy metals – A systematic review and meta-analysis","authors":"Peter Møller , Ezgi Eyluel Bankoglu , Helga Stopper , Goran Gajski , Marko Gerić , Anja Haveric , Amaya Azqueta , Lisa Giovannelli , Andrew Collins , Carina Ladeira","doi":"10.1016/j.mrrev.2025.108567","DOIUrl":"10.1016/j.mrrev.2025.108567","url":null,"abstract":"<div><div>Exposure to heavy metals such as lead, arsenic and chromium is associated with genotoxicity and increased risk of cancer. In this systematic review and meta-analysis, we have assessed effects of heavy metal exposure on levels of DNA strand breaks in leukocytes, measured by the comet assay, in human biomonitoring studies. We distinguish between traditional toxic metals (lead), semi-metals/metalloids (arsenic), transition metals (chromium), and other heavy metals. The literature search led to 66 studies, which were assessed by meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show increased levels of DNA strand breaks in subjects exposed to lead (1.99, 95 % CI: 1.47, 2.51), arsenic (1.36, 95 % CI: 0.94, 1.77), chromium/welding fume (2.03, 95 % CI: 1.48, 2.57), and other heavy metals (0.81, 95 % CI: 0.45, 1.18). Subgroup analysis indicates that all studies combined from middle-income countries have higher effect size (1.99, 95 % CI: 1.63, 2.35) than have studies from high-income countries (0.81, 95 % CI: 0.37, 1.26). The lower effect size in high-income countries may be due to differences in exposure levels, related to stricter regulation of emissions or more awareness/use of personal protective equipment in the working environment. Sensitivity analysis does not unequivocally link effect size to comet assay measurement bias, inferred by insufficient information on comet assay procedures, missing assay controls, non-blinded analysis of samples, or exposure misclassification. In conclusion, this systematic review and meta-analysis shows that exposure to heavy metals - lead, arsenic and chromium – is associated with increased levels of DNA strand breaks in human leukocytes.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108567"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145507686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108562
Li Wu , Lingli Wang , Jingyu Hou , Zhengping Shao , Jun Yang , Xiangwei Gao
To maintain genomic stability, cells have evolved complex mechanisms collectively known as the DNA damage response (DDR), which includes DNA repair, cell cycle checkpoints, apoptosis, and gene expression regulation. Recent studies have revealed that long non-coding RNAs (lncRNAs) are pivotal regulators of the DDR. Beyond their established roles in recruiting repair proteins and modulating gene expression, emerging evidence highlights two particularly intriguing functions. First, some lncRNAs contain small open reading frames (sORFs) encoding functional micropeptides that actively participate in DDR pathways. Second, lncRNAs regulate R-loop homeostasis, a key mechanism for preserving genome integrity. Together, these findings expand our understanding of lncRNAs in the DDR, positioning them as both key mechanistic players and promising therapeutic targets.
{"title":"Mechanistic roles of long non-coding RNAs in DNA damage response and genome stability","authors":"Li Wu , Lingli Wang , Jingyu Hou , Zhengping Shao , Jun Yang , Xiangwei Gao","doi":"10.1016/j.mrrev.2025.108562","DOIUrl":"10.1016/j.mrrev.2025.108562","url":null,"abstract":"<div><div>To maintain genomic stability, cells have evolved complex mechanisms collectively known as the DNA damage response (DDR), which includes DNA repair, cell cycle checkpoints, apoptosis, and gene expression regulation. Recent studies have revealed that long non-coding RNAs (lncRNAs) are pivotal regulators of the DDR. Beyond their established roles in recruiting repair proteins and modulating gene expression, emerging evidence highlights two particularly intriguing functions. First, some lncRNAs contain small open reading frames (sORFs) encoding functional micropeptides that actively participate in DDR pathways. Second, lncRNAs regulate R-loop homeostasis, a key mechanism for preserving genome integrity. Together, these findings expand our understanding of lncRNAs in the DDR, positioning them as both key mechanistic players and promising therapeutic targets.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108562"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108561
Micheline Kirsch-Volders , Michael Fenech , Miroslav Mišík , Paul Van Hummelen
Circulating cell-free DNA (cfDNA), particularly in blood, is emerging as a critical non-invasive biomarker for the prediction, diagnosis, and monitoring of human diseases. Additionally, cytoplasmic DNA has been implicated in promoting genetic aberrations, genome instability, and inflammation—factors that can contribute to the development of various diseases, including cancer. However, the heterogeneous nature of both intra- and extracellular DNA presents a significant challenge. This review synthesizes current evidence on the origin, composition, and fate of micronuclei (MN) and their derived DNA/chromatin, highlighting their potential as active participants in genomic instability and immune activation. We examine the molecular characteristics of MN, including their formation from acentric fragments, whole chromosomes, or double minutes, and their dynamic intracellular outcomes, such as reintegration, degradation, or extrusion. A major focus is placed on the consequences of micronuclear envelope rupture, including chromothripsis and cGAS-STING–mediated inflammation. We explore the emerging evidence for the extrusion of MN or MN-derived DNA via direct extrusion or packaging in extracellular vesicles, and discuss their implications for cfDNA composition, detection, and biomarker development. The review also underscores the relevance of MN in disease pathogenesis and senescence, and concludes by outlining critical knowledge gaps, particularly concerning the mechanisms of MN clearance, their tissue origin, and their survival and detectability in plasma. In conclusion, by elucidating the mechanistic link between MN biology and cfDNA, we propose that MN-derived DNA and chromatin may serve as informative indicators of genomic instability and disease progression, and offer valuable insights for future diagnostic and therapeutic strategies.
{"title":"The intracellular and extracellular fate of DNA and chromatin from micronuclei determines their pathogenicity","authors":"Micheline Kirsch-Volders , Michael Fenech , Miroslav Mišík , Paul Van Hummelen","doi":"10.1016/j.mrrev.2025.108561","DOIUrl":"10.1016/j.mrrev.2025.108561","url":null,"abstract":"<div><div>Circulating cell-free DNA (cfDNA), particularly in blood, is emerging as a critical non-invasive biomarker for the prediction, diagnosis, and monitoring of human diseases. Additionally, cytoplasmic DNA has been implicated in promoting genetic aberrations, genome instability, and inflammation—factors that can contribute to the development of various diseases, including cancer. However, the heterogeneous nature of both intra- and extracellular DNA presents a significant challenge. This review synthesizes current evidence on the origin, composition, and fate of micronuclei (MN) and their derived DNA/chromatin, highlighting their potential as active participants in genomic instability and immune activation. We examine the molecular characteristics of MN, including their formation from acentric fragments, whole chromosomes, or double minutes, and their dynamic intracellular outcomes, such as reintegration, degradation, or extrusion. A major focus is placed on the consequences of micronuclear envelope rupture, including chromothripsis and cGAS-STING–mediated inflammation. We explore the emerging evidence for the extrusion of MN or MN-derived DNA via direct extrusion or packaging in extracellular vesicles, and discuss their implications for cfDNA composition, detection, and biomarker development. The review also underscores the relevance of MN in disease pathogenesis and senescence, and concludes by outlining critical knowledge gaps, particularly concerning the mechanisms of MN clearance, their tissue origin, and their survival and detectability in plasma. In conclusion, by elucidating the mechanistic link between MN biology and cfDNA, we propose that MN-derived DNA and chromatin may serve as informative indicators of genomic instability and disease progression, and offer valuable insights for future diagnostic and therapeutic strategies.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108561"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Patients with inborn errors of immunity (IEI) experience severe infectious and non-infectious complications, leading to an increased risk of mortality. Delayed diagnosis or misdiagnosis significantly contributes to the heightened mortality rates observed in IEI patients.
Objectives
This study systematically reviews the causes of mortality in IEI patients with a meta-analysis to determine the mortality rate among patients with various IEI.
Methods
Embase, ISI Web of Science, PubMed, and Scopus were searched (up to July 2024) using terms related to IEI and mortality.
Results
A total of 12,581 deceased IEI patients were included, with an overall reported mortality rate of 24.0 % (95 % confidence interval: 23.0–26.0 %) among all published IEI cases. This represents an approximately 27-fold higher mortality rate among IEI patients compared to the mean global mortality rate (24 % vs. 0.874 %). Severe combined immunodeficiency, chronic granulomatous disease, and ataxia-telangiectasia had the highest numbers of reported deceased cases (2304, 962, and 820 cases, respectively). However, familial hemophagocytic lymphohistiocytosis exhibited the highest mortality rate (49.0 %). The most common causes of death were infections, transplant-related mortality and non-infectious pulmonary complications, (3429, 2749, and 1141 cases), respectively. Among infectious causes of death, COVID-19 infection accounted for 10.8 % (370 cases).
Conclusion
This study identifies specific types of IEI with the highest mortality rates and numbers, alongside immune component defects most strongly associated with increased mortality. Patients with immune dysregulation, defects in cellular immunity, and phagocyte function were particularly linked to higher mortality rates, underscoring the urgent need for improved management strategies for these IEIs.
背景：先天性免疫错误（IEI）患者会出现严重的传染性和非传染性并发症，导致死亡风险增加。延迟诊断或误诊显著提高了IEI患者的死亡率。目的：本研究通过荟萃分析系统地回顾了IEI患者的死亡原因，以确定各种IEI患者的死亡率。方法：检索Embase， ISI Web of Science， PubMed和Scopus（截至2024年7月），使用与IEI和死亡率相关的术语。结果：共纳入12,581例IEI死亡患者，在所有已发表的IEI病例中，报告的总死亡率为24.0 %（95% %可信区间：23.0-26.0 %）。与全球平均死亡率相比，IEI患者的死亡率大约高出27倍（24 %对0.874 %）。严重联合免疫缺陷、慢性肉芽肿病和共济失调毛细血管扩张的死亡病例最多（分别为2304例、962例和820例）。家族性噬血细胞淋巴组织细胞病死亡率最高（49.0 %）。最常见的死亡原因分别是感染、移植相关死亡和非感染性肺部并发症（3429例、2749例和1141例）。在感染性死亡原因中，COVID-19感染占10.8 %（370例）。结论：本研究确定了特定类型的IEI具有最高的死亡率和数量，以及与死亡率增加最密切相关的免疫成分缺陷。免疫失调、细胞免疫缺陷和吞噬细胞功能缺陷的患者尤其与较高的死亡率有关，这突出表明迫切需要改进这些肠内感染的管理策略。
{"title":"Mortality rate and causes of death in inborn errors of immunity: A systematic review and meta-analysis","authors":"Saba Fekrvand , Zahra Hamidi Esfahani , Mohammadmehdi Yarahmadi , Ali Saeedi-Boroujeni , Helia Salehi , Ali Hakimelahi , Amir Almasi-Hashiani , Mahshid Rahmati , Sanaz Afshar-Ghasemlou , Najmeh Nameh Goshay Fard , Fateme Tarighat Monfared , Ehsan Khoshnezhad Afkham , Nazanin Fathi , Tannaz Moeini Shad , Fateme Babaha , Farzad Nazari , Matineh Nirouei , Amir Salehi Farid , Negin Sanadgol , Hosein Rafiemanesh , Reza Yazdani","doi":"10.1016/j.mrrev.2025.108564","DOIUrl":"10.1016/j.mrrev.2025.108564","url":null,"abstract":"<div><h3>Background</h3><div>Patients with inborn errors of immunity (IEI) experience severe infectious and non-infectious complications, leading to an increased risk of mortality. Delayed diagnosis or misdiagnosis significantly contributes to the heightened mortality rates observed in IEI patients.</div></div><div><h3>Objectives</h3><div>This study systematically reviews the causes of mortality in IEI patients with a meta-analysis to determine the mortality rate among patients with various IEI.</div></div><div><h3>Methods</h3><div>Embase, ISI Web of Science, PubMed, and Scopus were searched (up to July 2024) using terms related to IEI and mortality.</div></div><div><h3>Results</h3><div>A total of 12,581 deceased IEI patients were included, with an overall reported mortality rate of 24.0 % (95 % confidence interval: 23.0–26.0 %) among all published IEI cases. This represents an approximately 27-fold higher mortality rate among IEI patients compared to the mean global mortality rate (24 % vs. 0.874 %). Severe combined immunodeficiency, chronic granulomatous disease, and ataxia-telangiectasia had the highest numbers of reported deceased cases (2304, 962, and 820 cases, respectively). However, familial hemophagocytic lymphohistiocytosis exhibited the highest mortality rate (49.0 %). The most common causes of death were infections, transplant-related mortality and non-infectious pulmonary complications, (3429, 2749, and 1141 cases), respectively. Among infectious causes of death, COVID-19 infection accounted for 10.8 % (370 cases).</div></div><div><h3>Conclusion</h3><div>This study identifies specific types of IEI with the highest mortality rates and numbers, alongside immune component defects most strongly associated with increased mortality. Patients with immune dysregulation, defects in cellular immunity, and phagocyte function were particularly linked to higher mortality rates, underscoring the urgent need for improved management strategies for these IEIs.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108564"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108551
Salma M.S. Ahmad , Fatemeh Abdullah M. Ahmadi , Roberta Giordo , Gavino Casu , Gheyath K. Nasrallaha , Hatem Zayed , Gianfranco Pintus
Non-coding RNAs (ncRNAs) have redefined the complexity of gene regulation, with the long non-coding (lncRNA) GAS5/miR-21 axis emerging as a critical determinant of cell fate across diverse pathological contexts. This review examines the molecular mechanisms by which GAS5 regulates miR-21 activity, thereby restoring tumor suppressor networks and controlling key pathways, including the PI3K/AKT, MAPK/ERK, and Wnt/β-catenin pathways. We detail how dysregulation of this axis fuels cancer progression, metastasis, therapy resistance, fibrosis, cardiovascular diseases, osteoporosis, osteoarthritis, and autoimmune conditions like systemic lupus erythematosus. Beyond its role as a master regulator of apoptosis, proliferation, and EMT, the GAS5/miR-21 interaction holds immense promise as a therapeutic target and a liquid biopsy biomarker. However, clinical translation demands solutions to major challenges, including RNA delivery barriers, context-dependent effects, and adaptive resistance. Leveraging multi-omics integration, gene-editing technologies, and personalized RNA therapeutics will be pivotal to overcoming these obstacles. By critically integrating current knowledge and outlining future directions, this review positions the GAS5/miR-21 axis at the forefront of next-generation ncRNA therapeutics. Harnessing its full potential could not only revolutionize treatment paradigms but also transform our understanding of RNA-driven disease networks.
{"title":"Molecular insights and emerging therapeutic perspectives of the lncRNA GAS5/miR-21 axis in cancer, fibrosis, cardiovascular, and immune disorders","authors":"Salma M.S. Ahmad , Fatemeh Abdullah M. Ahmadi , Roberta Giordo , Gavino Casu , Gheyath K. Nasrallaha , Hatem Zayed , Gianfranco Pintus","doi":"10.1016/j.mrrev.2025.108551","DOIUrl":"10.1016/j.mrrev.2025.108551","url":null,"abstract":"<div><div>Non-coding RNAs (ncRNAs) have redefined the complexity of gene regulation, with the long non-coding (lncRNA) GAS5/miR-21 axis emerging as a critical determinant of cell fate across diverse pathological contexts. This review examines the molecular mechanisms by which GAS5 regulates miR-21 activity, thereby restoring tumor suppressor networks and controlling key pathways, including the PI3K/AKT, MAPK/ERK, and Wnt/β-catenin pathways. We detail how dysregulation of this axis fuels cancer progression, metastasis, therapy resistance, fibrosis, cardiovascular diseases, osteoporosis, osteoarthritis, and autoimmune conditions like systemic lupus erythematosus. Beyond its role as a master regulator of apoptosis, proliferation, and EMT, the GAS5/miR-21 interaction holds immense promise as a therapeutic target and a liquid biopsy biomarker. However, clinical translation demands solutions to major challenges, including RNA delivery barriers, context-dependent effects, and adaptive resistance. Leveraging multi-omics integration, gene-editing technologies, and personalized RNA therapeutics will be pivotal to overcoming these obstacles. By critically integrating current knowledge and outlining future directions, this review positions the GAS5/miR-21 axis at the forefront of next-generation ncRNA therapeutics. Harnessing its full potential could not only revolutionize treatment paradigms but also transform our understanding of RNA-driven disease networks.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108551"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108563
Ahmad M. Alamri , Abdullah A. Assiri , Najeeb Ullah Khan
Objective
To assess the variations in Single Nucleotide Polymorphisms (SNPs) that affect susceptibility of CRC in Saudi patients.
Methods
A systematic literature review was conducted following PRISMA guidelines. Electronic databases were searched from inception up to March 2025 using MeSH terms and keywords related to SNPs, Colorectal Cancer (CRC), and Saudi Arabia. Eligibility criteria mandated studies conducted on Saudi populations, including confirmed CRC cases and healthy controls (≥18 years), investigating SNP-CRC associations, and reporting risk estimates. Data on study characteristics, gene/SNP details, participant numbers, genotyping methods, risk estimates, p-values, and pathway categorization were extracted by two independent reviewers. The Newcastle-Ottawa Scale was used to assess the risk of bias in included case-control studies.
Results
Twenty-three case-control studies met the inclusion criteria, encompassing 2521 CRC cases and 2236 healthy controls. These studies investigated SNPs within 46 different genes. Significant associations (p < 0.05) with CRC risk were identified across various biological pathways. SNPs in inflammation/immune response genes (e.g., TNF-α, IL-17A, PD-1, CTLA-4, IL-10, TGFβ1) showed both increased and decreased risk associations. Variations in DNA repair (PARP-1, XRCC1, TP53) and cellular protection/drug metabolism genes (ABCC1, MDR1, GSTM1) also modulated susceptibility. Furthermore, SNPs in signaling pathways (VDR, MMP-2, NOTCH) and membrane/RNA-related genes (HER1, HER2, RETN, PRNCR1, HOTAIR) were significantly associated with CRC risk. Some allele frequencies (CYP19A) appeared distinct in the Saudi population compared to others. Most studies (77 %) were assessed as having a low risk of bias, though hospital-based control recruitment was a common limitation.
Conclusion
This systematic review confirms that numerous SNPs are significantly associated with altered CRC susceptibility in the Saudi population. These findings highlight a complex genetic landscape and underscore the potential value of identified SNPs for developing population-specific CRC risk assessment tools and targeted screening programs in Saudi Arabia.
{"title":"Single nucleotide variants associated with colorectal cancer among Saudi patients: A systematic review","authors":"Ahmad M. Alamri , Abdullah A. Assiri , Najeeb Ullah Khan","doi":"10.1016/j.mrrev.2025.108563","DOIUrl":"10.1016/j.mrrev.2025.108563","url":null,"abstract":"<div><h3>Objective</h3><div>To assess the variations in Single Nucleotide Polymorphisms (SNPs) that affect susceptibility of CRC in Saudi patients.</div></div><div><h3>Methods</h3><div>A systematic literature review was conducted following PRISMA guidelines. Electronic databases were searched from inception up to March 2025 using MeSH terms and keywords related to SNPs, Colorectal Cancer (CRC), and Saudi Arabia. Eligibility criteria mandated studies conducted on Saudi populations, including confirmed CRC cases and healthy controls (≥18 years), investigating SNP-CRC associations, and reporting risk estimates. Data on study characteristics, gene/SNP details, participant numbers, genotyping methods, risk estimates, p-values, and pathway categorization were extracted by two independent reviewers. The Newcastle-Ottawa Scale was used to assess the risk of bias in included case-control studies.</div></div><div><h3>Results</h3><div>Twenty-three case-control studies met the inclusion criteria, encompassing 2521 CRC cases and 2236 healthy controls. These studies investigated SNPs within 46 different genes. Significant associations (p < 0.05) with CRC risk were identified across various biological pathways. SNPs in inflammation/immune response genes (e.g., <em>TNF-α</em>, <em>IL-17A</em>, <em>PD-1</em>, <em>CTLA-4</em>, <em>IL-10</em>, <em>TGFβ1</em>) showed both increased and decreased risk associations. Variations in DNA repair (<em>PARP-1, XRCC1, TP53</em>) and cellular protection/drug metabolism genes (<em>ABCC1, MDR1, GSTM1</em>) also modulated susceptibility. Furthermore, SNPs in signaling pathways (<em>VDR, MMP-2, NOTCH</em>) and membrane/RNA-related genes (<em>HER1, HER2, RETN, PRNCR1, HOTAIR</em>) were significantly associated with CRC risk. Some allele frequencies (CYP19A) appeared distinct in the Saudi population compared to others. Most studies (77 %) were assessed as having a low risk of bias, though hospital-based control recruitment was a common limitation.</div></div><div><h3>Conclusion</h3><div>This systematic review confirms that numerous SNPs are significantly associated with altered CRC susceptibility in the Saudi population. These findings highlight a complex genetic landscape and underscore the potential value of identified SNPs for developing population-specific CRC risk assessment tools and targeted screening programs in Saudi Arabia.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108563"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Neutrophil extracellular traps (NETs) and the process of NETosis have emerged as critical participants in various pathological conditions. Resveratrol, a natural polyphenol found in several plants, has received significant attention due to its potential therapeutic properties. The purpose of this review is to investigate how resveratrol affects NETs and NETosis. The molecular mechanisms underlying NET formation and its role in disease pathogenesis are discussed, highlighting the involvement of various cellular and molecular factors. Moreover, the effects of resveratrol on NET formation, release, and stability are reported, focusing on its potential as a modulator of NET-associated diseases. Studies investigating the effect of resveratrol on NETosis in different disease models, including lung injury, COVID-19, cancer, and hepatic ischemia-reperfusion injury, are also summarized. Furthermore, the potential mechanisms through which resveratrol exerts its effects on NETosis, including anti-inflammatory, antioxidant, and immunomodulatory properties, are elucidated. The review also addresses the challenges and future perspectives in the field, emphasizing the need for further research to fully understand the therapeutic potential of resveratrol in targeting NET-associated disorders. Generally, this review provides a comprehensive analysis of the impact of resveratrol on NETs and NETosis, shedding light on its potential as a therapeutic intervention in various pathological conditions characterized by excessive NET formation. However, further research is essential to clarify the detailed mechanisms through which resveratrol exerts its effects on NETosis and to determine optimal dosages and treatment procedures.
{"title":"Impact of resveratrol on neutrophil extracellular traps","authors":"Mahboobeh Ghasemzadeh Rahbardar , Prashant Kesharwani , Amirhossein Sahebkar","doi":"10.1016/j.mrrev.2025.108550","DOIUrl":"10.1016/j.mrrev.2025.108550","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) and the process of NETosis have emerged as critical participants in various pathological conditions. Resveratrol, a natural polyphenol found in several plants, has received significant attention due to its potential therapeutic properties. The purpose of this review is to investigate how resveratrol affects NETs and NETosis. The molecular mechanisms underlying NET formation and its role in disease pathogenesis are discussed, highlighting the involvement of various cellular and molecular factors. Moreover, the effects of resveratrol on NET formation, release, and stability are reported, focusing on its potential as a modulator of NET-associated diseases. Studies investigating the effect of resveratrol on NETosis in different disease models, including lung injury, COVID-19, cancer, and hepatic ischemia-reperfusion injury, are also summarized. Furthermore, the potential mechanisms through which resveratrol exerts its effects on NETosis, including anti-inflammatory, antioxidant, and immunomodulatory properties, are elucidated. The review also addresses the challenges and future perspectives in the field, emphasizing the need for further research to fully understand the therapeutic potential of resveratrol in targeting NET-associated disorders. Generally, this review provides a comprehensive analysis of the impact of resveratrol on NETs and NETosis, shedding light on its potential as a therapeutic intervention in various pathological conditions characterized by excessive NET formation. However, further research is essential to clarify the detailed mechanisms through which resveratrol exerts its effects on NETosis and to determine optimal dosages and treatment procedures.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108550"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-01DOI: 10.1016/j.mrrev.2025.108565
Marko Gerić , Amaya Azqueta , Peter Møller , Ezgi Eyluel Bankoglu , Goran Gajski , Lisa Giovannelli , Anja Haverić , Helga Stopper , Andrew Collins , Carina Ladeira
Exposure to pesticides, most usually in occupational settings, is associated with different adverse health effects. In this systematic review and meta-analysis, we have assessed the effects of pesticide exposure on the level of DNA strand breaks in human peripheral blood cells, measured by the comet assay, in human biomonitoring studies. The literature search led to 80 studies included in the review. Of these, 66 studies met the criteria to be used in the meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show an increased level of DNA strand breaks in subjects exposed to pesticides (2.02, 95 % CI: 1.69, 2.35). Results originate mainly from studies on workers, with only a few studies on environmental pesticide exposure. Subgroup analysis indicates that all studies combined from middle-income countries have a higher effect size (2.22, CI: 1.84, 2.59, n = 55) than studies from high-income countries (1.09, CI: 0.41, 1.76, n = 11). This difference between middle- and high-income countries may be mostly due to legislative, economic, and socio-cultural aspects. It has to be pointed out that only 9 % of the studies were classified as having an overall low risk of bias, while 12 % of studies used exposure biomarkers. In conclusion, this systematic review and meta-analysis shows that exposure to pesticides is associated with increased levels of DNA strand breaks in human peripheral blood cells.
接触农药（通常是在职业环境中）与不同的不利健康影响有关。在这篇系统综述和荟萃分析中，我们评估了农药暴露对人类外周血细胞DNA链断裂水平的影响，通过彗星测定法测量，在人类生物监测研究中。文献检索导致80项研究被纳入综述。其中，66项研究符合meta分析的标准。使用标准化平均差和95 %置信区间（CI）， meta分析显示暴露于农药的受试者DNA链断裂水平增加（2.02,95 % CI: 1.69, 2.35）。结果主要来源于对工人的研究，对环境农药暴露的研究很少。亚组分析表明，所有来自中等收入国家的综合研究的效应量（2.22,CI: 1.84, 2.59, n = 55）高于来自高收入国家的研究（1.09,CI: 0.41, 1.76, n = 11）。中等收入国家和高收入国家之间的这种差异可能主要是由于立法、经济和社会文化方面的原因。必须指出的是，只有9 %的研究被归类为总体低偏倚风险，而12 %的研究使用了暴露生物标志物。总之，本系统综述和荟萃分析表明，暴露于农药与人类外周血中DNA链断裂水平增加有关。
{"title":"The comet assay as a tool in human biomonitoring exposure to pesticides–A systematic review and meta-analysis","authors":"Marko Gerić , Amaya Azqueta , Peter Møller , Ezgi Eyluel Bankoglu , Goran Gajski , Lisa Giovannelli , Anja Haverić , Helga Stopper , Andrew Collins , Carina Ladeira","doi":"10.1016/j.mrrev.2025.108565","DOIUrl":"10.1016/j.mrrev.2025.108565","url":null,"abstract":"<div><div>Exposure to pesticides, most usually in occupational settings, is associated with different adverse health effects. In this systematic review and meta-analysis, we have assessed the effects of pesticide exposure on the level of DNA strand breaks in human peripheral blood cells, measured by the comet assay, in human biomonitoring studies. The literature search led to 80 studies included in the review. Of these, 66 studies met the criteria to be used in the meta-analysis. Using standardized mean difference and 95 % confidence interval (CI), the meta-analyses show an increased level of DNA strand breaks in subjects exposed to pesticides (2.02, 95 % CI: 1.69, 2.35). Results originate mainly from studies on workers, with only a few studies on environmental pesticide exposure. Subgroup analysis indicates that all studies combined from middle-income countries have a higher effect size (2.22, CI: 1.84, 2.59, n = 55) than studies from high-income countries (1.09, CI: 0.41, 1.76, n = 11). This difference between middle- and high-income countries may be mostly due to legislative, economic, and socio-cultural aspects. It has to be pointed out that only 9 % of the studies were classified as having an overall low risk of bias, while 12 % of studies used exposure biomarkers. In conclusion, this systematic review and meta-analysis shows that exposure to pesticides is associated with increased levels of DNA strand breaks in human peripheral blood cells.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108565"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145304234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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