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The Effect of X rays on the Expression of Mismatch Repair Genes and Proteins in Lynch Syndrome Associated Human Colorectal Cancer Cell Lines. X射线对Lynch综合征相关人结直肠癌细胞系错配修复基因和蛋白表达的影响
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-20 DOI: 10.1667/RADE-25-00097.1
Mingzhu Sun, Lourdes Cruz-Garcia, Danny Freestone, Kevin Monahan, Christophe Badie, Yannick Comoglio, Hannah Mancey, Jayne Moquet, Stephen Barnard
{"title":"The Effect of X rays on the Expression of Mismatch Repair Genes and Proteins in Lynch Syndrome Associated Human Colorectal Cancer Cell Lines.","authors":"Mingzhu Sun, Lourdes Cruz-Garcia, Danny Freestone, Kevin Monahan, Christophe Badie, Yannick Comoglio, Hannah Mancey, Jayne Moquet, Stephen Barnard","doi":"10.1667/RADE-25-00097.1","DOIUrl":"https://doi.org/10.1667/RADE-25-00097.1","url":null,"abstract":"<p><p>This study investigated whether therapeutic X-ray doses can affect the expression of mismatch repair (MMR) genes and proteins using Lynch syndrome-associated human colorectal cancer cell lines. MMR-deficient cell lines (HCT116, SW48, LoVo) and an MMR-proficient control cell line (HT29) were exposed to X rays [a 2 Gy dose or 2 Gy daily for five consecutive days (10 Gy)]. Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting were used to detect the radiation-induced changes in the expression of RNAs and proteins, respectively. RT-qPCR revealed that MLH1 and MSH6 genes were stably expressed regardless of the MMR status of the cell line and the radiation dose. In contrast, the MSH2 gene was either up-regulated or down-regulated after 2 Gy or 10 Gy or both. The expression of PMS2 increased after 10 Gy irradiation in all MMR-deficient cell lines, even though the data were not statistically significant compared to other doses, except for the LoVo cell line. Protein expression analysed using Western blotting demonstrated that MLH1 protein expression was stable, whereas the expression of MSH2 was significantly affected by radiation exposure in both MLH1-deficient cell lines. No correlation between the expression of RNA and protein could be identified. In conclusion, radiation may have significantly differential effects on MMR RNA and protein expression when different cell lines, doses, and specific genes are considered.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144340372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Raman Spectroscopic Biodosimetry Using Protein in Murine Hair. 拉曼光谱法测定小鼠毛发中蛋白质的生物剂量。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-19 DOI: 10.1667/RADE-25-00046.1
Spencer A Witte, Monika Poonia, Mallard Woodward, Lanchun Lu, Marshleen Yadav, Naduparambil K Jacob, Zachary D Schultz
{"title":"Raman Spectroscopic Biodosimetry Using Protein in Murine Hair.","authors":"Spencer A Witte, Monika Poonia, Mallard Woodward, Lanchun Lu, Marshleen Yadav, Naduparambil K Jacob, Zachary D Schultz","doi":"10.1667/RADE-25-00046.1","DOIUrl":"https://doi.org/10.1667/RADE-25-00046.1","url":null,"abstract":"<p><p>Hair is an attractive sample for determining exposure to ionizing radiation due to its non-invasive nature. A biological tissue comprised mainly of keratin protein, hair is susceptible to oxidative or reductive stress by direct or indirect damage mechanisms. In this report, changes observed in the Raman spectra associated with hair protein from ionizing radiation were assessed for biodosimetry. Raman spectra were obtained from the hairs of a mixed sex cohort of irradiated C57BL/6 mice (N = 32 total) with doses of gamma rays ranging from 0-4 Gy. Radiation-dependent changes in the Raman spectra of the hairs provided molecular-specific signals that can inform about the damage mechanism. Partial least-squares discriminant analysis (PLS-DA) models incorporating automated variable selection for each sex showed classification of controls or exposed at 80% accuracy based on cross-validation. Models show only slight differences in performance based on the mouse's sex from which the sample originated. This slight difference is consistent with PLS-DA models that show marginal cross-validation sensitivity (∼60%) in predicting the sex of the mouse from the Raman hair spectrum. Utilizing PLS regression, a dose-response model including both sexes showed root-mean-squared error (RMSE) ±1 Gy. The ability to determine dose or exposure from plucked hair with Raman spectroscopy would provide a needed tool for rapid medical triage after unexpected exposure.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144326737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Comparative Study of Pathology of Various Organs of Rhesus and Cynomolgus Nonhuman Primates Exposed to Two Different Doses of Acute Total-body Radiation. 两种不同剂量急性全身辐射对猕猴和食蟹类非人灵长类动物各器官病理的比较研究。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-16 DOI: 10.1667/RADE-25-00062.1
Vijay K Singh, Stephen Y Wise, Oluseyi O Fatanmi, Sarah A Petrus, Issa Melendez-Miranda, Alana D Carpenter, Sang-Ho Lee, Thomas M Seed
{"title":"Comparative Study of Pathology of Various Organs of Rhesus and Cynomolgus Nonhuman Primates Exposed to Two Different Doses of Acute Total-body Radiation.","authors":"Vijay K Singh, Stephen Y Wise, Oluseyi O Fatanmi, Sarah A Petrus, Issa Melendez-Miranda, Alana D Carpenter, Sang-Ho Lee, Thomas M Seed","doi":"10.1667/RADE-25-00062.1","DOIUrl":"https://doi.org/10.1667/RADE-25-00062.1","url":null,"abstract":"<p><p>The rhesus macaque (Macaca mulatta) is the primary nonhuman primate (NHP) model used for the development of radiation medical countermeasures (MCMs), but due to the limited supply of rhesus macaques that has resulted from their need in other high priority medical research areas, alternative animal models for MCM development have been sought. The cynomolgus macaque (Macaca fascicularis) is less well characterized and less commonly used, but represents another quite viable, large animal NHP model for investigating MCMs. We have investigated the nature of injuries within selected organ systems induced by two potentially lethal doses (5.8 and 6.5 Gy) of ionizing radiation delivered as a total-body exposure to both rhesus and cynomolgus NHPs. Results suggest that the injuries within organs with strong self-renewing capacities (gastrointestinal and lymphohematopoietic systems) were comparable between the two NHP species, although the severity of the injuries differed. By contrast, the nature and seriousness of noted tissue pathologies were more comparable for other tissues with more limited self-renewal. In aggregate, however, the observed radiation-associated pathologies in various organs appeared to be more prominent within cynomolgus NHPs and hence, were somewhat more sensitive to the radiation exposures compared to rhesus NHPs.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
A Microdosimetric Dose Response Model for Monoenergetic Ions and Doses Relevant for Space Radiation Carcinogenesis. 单能离子的微剂量反应模型和与空间辐射致癌有关的剂量。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-06 DOI: 10.1667/RADE-25-00021.1
T C Slaba, F Poignant, S Rahmanian
{"title":"A Microdosimetric Dose Response Model for Monoenergetic Ions and Doses Relevant for Space Radiation Carcinogenesis.","authors":"T C Slaba, F Poignant, S Rahmanian","doi":"10.1667/RADE-25-00021.1","DOIUrl":"https://doi.org/10.1667/RADE-25-00021.1","url":null,"abstract":"<p><p>The radiation environment in space consists of a complex mixture of particles and energies that are characteristically different from any natural Earth radiation source. Projections of space radiation cancer risk are obtained by scaling or adjusting epidemiological models derived from terrestrially exposed cohorts to account for differences in radiation quality, dose rate, and other factors. Radiation quality and dose-rate effects introduce significant uncertainty, thereby obfuscating risk communication and hindering the ability to evaluate the efficacy of mitigation strategies such as medical countermeasures. Space radiation quality factors are developed through a multi-step process that requires computational models and experimental data. The first step in this process involves developing dose-response models and fitting them to data from ground-based experiments involving acute irradiation of animals or cells. There is limited ground-based data compared to the range of ions and energies found in space; thus, dose-response models must be able to reproduce available data and predict responses where no data exist. This work focuses on developing a microdosimetric (D) dose-response model applicable to experimental datasets relevant to space radiation cancer induction. Three experimental datasets, encompassing murine Harderian gland tumorigenesis and chromosome aberrations in human skin fibroblasts and blood lymphocytes, are utilized to demonstrate key features and overall performance of the D model. The model generates non-linear dose-responses and can predict charge and energy dependence observed in experimental data without the use of empirical functions or corrections. Additionally, the D model identifies the critical microscopic target population and target size that drive the observed biological effects.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234963","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
PNA-FISH-based Chromosome Aberration Frequency and Serum IL-6 as Predictive Biomarkers for Radiation Therapy-induced Pneumonitis in Lung Cancer Patients. 基于pna - fish的染色体畸变频率和血清IL-6作为肺癌患者放射治疗性肺炎的预测性生物标志物
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-06 DOI: 10.1667/RADE-25-00013.1
Gloriamaris Loy-Caraos, Nobuki Imano, Ikuno Nishibuchi, Yuji Murakami, Nafiseh Mirkatouli, Seiko Hirota, Shinji Yoshinaga, Yoshitaka Kamimura, Yuri Kawashima, Jiying Sun, Satoshi Tashiro
{"title":"PNA-FISH-based Chromosome Aberration Frequency and Serum IL-6 as Predictive Biomarkers for Radiation Therapy-induced Pneumonitis in Lung Cancer Patients.","authors":"Gloriamaris Loy-Caraos, Nobuki Imano, Ikuno Nishibuchi, Yuji Murakami, Nafiseh Mirkatouli, Seiko Hirota, Shinji Yoshinaga, Yoshitaka Kamimura, Yuri Kawashima, Jiying Sun, Satoshi Tashiro","doi":"10.1667/RADE-25-00013.1","DOIUrl":"https://doi.org/10.1667/RADE-25-00013.1","url":null,"abstract":"<p><p>Accurate prediction of symptomatic radiation therapy-induced pneumonitis (RT-IP) remains an important clinical challenge. Currently, mean lung dose and volume of the lungs receiving a 20 Gy threshold of ≤20 Gy and ≤35%, respectively, are utilized to reduce the incidence of pneumonitis to 20%. However, its occurrence is not entirely predictable even at the recommended threshold levels. Hence, in this study, we aimed to evaluate several biological markers, specifically chromosome aberrations by peptide nucleic acid fluorescence in situ hybridization (PNA-FISH), γH2AX, serum IL-6, and IL-17, as potential predictors of symptomatic (grade ≥2) radiation therapy-induced pneumonitis. We prospectively enrolled patients with locally advanced lung cancer. Peripheral blood samples were collected from eleven patients before, during (2 Gy, 20 Gy, 60/66 Gy), and one month after chemoradiotherapy. We then compared these biomarkers between overreactors (grade ≥2 RT-IP) and non-overreactors (grade 0 to 1 RT-IP). Our findings show that chromosome aberration frequency, serum IL-6, and IL-17 after 20 Gy are higher in overreactors than in non-overreactors. Moreover, overreactors accumulated more complex aberrations, such as tricentrics, quadricentrics, and quintacentrics. While chromosome aberration frequency correlated with mean lung dose and IL-17, a pneumonitis marker, IL-6 correlated with the irradiated volume after 20 Gy. Receiver operating characteristic curve analysis further showed that chromosome aberration frequency and IL-6 have the highest specificity for predicting grade ≥2 RT-IP among the assays. In conclusion, we demonstrated the superior predictive capability of PNA-FISH-based chromosome aberration frequency and serum IL-6 for radiation therapy-induced pneumonitis in lung cancer patients. This supports the usefulness of these biomarkers for predicting radiation therapy-induced pneumonitis.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Understudied Populations in Radiation Exposure Research: Needs, Challenges, and Mitigation Strategies. 辐射暴露研究中未充分研究的人群:需求、挑战和缓解策略。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-04 DOI: 10.1667/RADE-24-00263.1
Lanyn P Taliaferro, Jeffrey C Buchsbaum, Andrea L DiCarlo, Cinnamon A Dixon, Francesca Macchiarini, Merriline M Satyamitra, Mercy PrabhuDas, Michael W Rudokas
{"title":"Understudied Populations in Radiation Exposure Research: Needs, Challenges, and Mitigation Strategies.","authors":"Lanyn P Taliaferro, Jeffrey C Buchsbaum, Andrea L DiCarlo, Cinnamon A Dixon, Francesca Macchiarini, Merriline M Satyamitra, Mercy PrabhuDas, Michael W Rudokas","doi":"10.1667/RADE-24-00263.1","DOIUrl":"https://doi.org/10.1667/RADE-24-00263.1","url":null,"abstract":"<p><p>This workshop examined the effects of ionizing radiation on certain understudied populations, including pregnant/lactating, in utero, pediatric, and geriatric populations. Research using animal models has revealed significant age and condition-related differences in radiation-induced injuries, highlighting the need for tailored triage and treatment strategies. Historical data from Hiroshima, Nagasaki, and Chernobyl further support these findings, demonstrating that radiation effects lead to wide-ranging issues with unique profiles during pregnancy, childhood and elderly age. While some research has been conducted on these groups, ethical and logistical challenges make it difficult to study these populations extensively. Therefore, developing alternative approaches that offer promising avenues for further research is critical. Radiation-induced biomarkers and biodosimetry also show age-related differences, including distinctive metabolic disruptions, necessitating further validation of biodosimetry tools. These findings emphasize the importance of considering age, sex, and demographic factors in preclinical and clinical radiation research to develop treatments that improve outcomes of understudied populations after a radiological or nuclear public health emergency.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144216722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Quantifying Sensitivity of Carbon RBE Models to Reference Parameter Variations. 量化碳RBE模型对参考参数变化的敏感性。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-02 DOI: 10.1667/RADE-24-00162.1
Shannon Hartzell, Fada Guan, Giuseppe Magro, Paige Taylor, Christine B Peterson, Stephen F Kry
{"title":"Quantifying Sensitivity of Carbon RBE Models to Reference Parameter Variations.","authors":"Shannon Hartzell, Fada Guan, Giuseppe Magro, Paige Taylor, Christine B Peterson, Stephen F Kry","doi":"10.1667/RADE-24-00162.1","DOIUrl":"https://doi.org/10.1667/RADE-24-00162.1","url":null,"abstract":"<p><p>Models used to calculate the relative biological effectiveness (RBE) of carbon-ion radiotherapy include the microdosimetric kinetic model (MKM), stochastic MKM (SMKM), repair-misrepair-fixation (RMF) model, and local effect model I (LEM). We compared the sensitivities of these models to variations in input biological and reference parameters. We used Monte Carlo simulations of clinically realistic carbon-ion beams incident on a phantom and scored input parameters for RBE models (kinetic energy, microdosimetric spectra, double-strand break yield, and physical dose). We combined data with cell- and model-specific parameters to calculate the linear (α) and quadratic (β) components of the carbon-ion beam, which were used along with the reference α and β values and dose to calculate RBE. Model sensitivity to parameters was quantified by statistically introducing uncertainty into independent parameters and sampling the resultant RBE. To assess histological differences contributing to variations in the RBE, we also used various reference cell lines. We recalculated the RBE using different reported datasets within individual cell lines to compare inter- and intra-cell line variability. The variability introduced by inherent measurement and estimation uncertainty was typically 26% for the microdosimetric models, 25% for the RMF model, and 30% for the LEM at the 1-σ level. The variability across cell lines, which averaged 27% for the microdosimetric models and 2.5% for the RMF model, was similar to the intra-cell line variability in the RBE as calculated with unique datasets for an individual cell line. While the focus is largely on comparing models, the results of this study indicate that the variation in RBE within each model, based solely on reference parameters, is substantial. Our findings indicate that the selection of input parameters is of comparable importance to the choice of cell line and even the RBE model. This study provides insight into model robustness and emphasizes the need for continued computational and in-vitro RBE research.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
Maternal High-fat Diet Modulates Radiosensitivity of Hematopoietic Tissue in Male Offspring. 母体高脂肪饮食调节雄性后代造血组织的放射敏感性。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-01 DOI: 10.1667/RADE-24-00163.1
Takanori Katsube, Masahiro Murakami, Kaoru Tanaka, Takamitsu Morioka, Shizuko Kakinuma, Bing Wang
{"title":"Maternal High-fat Diet Modulates Radiosensitivity of Hematopoietic Tissue in Male Offspring.","authors":"Takanori Katsube, Masahiro Murakami, Kaoru Tanaka, Takamitsu Morioka, Shizuko Kakinuma, Bing Wang","doi":"10.1667/RADE-24-00163.1","DOIUrl":"10.1667/RADE-24-00163.1","url":null,"abstract":"<p><p>Obesity is a growing global health concern, and the Western diet characterized by its high-calorie and high-fat content, is widely acknowledged as a major contributor. Obesity is closely linked to the onset of various metabolic syndromes in affected individuals. Furthermore, maternal obesity has been revealed to have persistent effects on the long-term health of offspring, a phenomenon widely recognized as the \"developmental origins of health and disease\" (DOHaD). In this study, we aimed to explore the potential modifying effects of maternal exposure to a high-fat diet (HFD) on the health outcomes of offspring after exposure to ionizing radiation. C57BL/6J female mice were fed either an HFD or a standard diet (STD) immediately after weaning at 3 weeks of age. At 10 weeks of age, they were mated with C3H/He male mice raised on an STD. The resulting pups were nursed by their dams and were subjected to a total body X-ray dose of 3.8 Gy at 7 days after birth. All pups were weaned onto an STD at 4 weeks of age, irrespective of their experimental group. Lifelong observation of these pups demonstrated that maternal exposure to HFD reduced the lifespan of male offspring postirradiation, whereas maternal HFD alone did not significantly impact the lifespan of both male and female offspring. Pathological analysis revealed that the lifespan shortening by maternal HFD after X irradiation was primarily attributed to early deaths associated with depletion of bone marrow cells and thymic lymphoma within 6 months after X irradiation. To the best of our knowledge, this is the first report showcasing the modifying effects of maternal HFD on the radiosensitivity of offspring.</p>","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"398-409"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144050840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
The Radioprotective Effects of 16, 16 dimethyl Prostaglandin E2 on Survival and Hematopoiesis are Mediated Through Co-Stimulation of the EP3 and EP4 Receptors. 16,16二甲基前列腺素E2通过共同刺激EP3和EP4受体介导的放射保护作用对生存和造血的影响。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-01 DOI: 10.1667/RADE-24-00176.1.S1
Seiji Fukuda, Andrea M Patterson, Tong Wu, Pratibha Singh, P Artur Plett, Hailin Feng, Carol H Sampson, Christie M Orschell, Louis M Pelus
{"title":"The Radioprotective Effects of 16, 16 dimethyl Prostaglandin E2 on Survival and Hematopoiesis are Mediated Through Co-Stimulation of the EP3 and EP4 Receptors.","authors":"Seiji Fukuda, Andrea M Patterson, Tong Wu, Pratibha Singh, P Artur Plett, Hailin Feng, Carol H Sampson, Christie M Orschell, Louis M Pelus","doi":"10.1667/RADE-24-00176.1.S1","DOIUrl":"10.1667/RADE-24-00176.1.S1","url":null,"abstract":"&lt;p&gt;&lt;p&gt;16, 16 dimethyl-Prostaglandin E2 (dmPGE2) administered prior to lethal irradiation protects against mortality from the hematopoietic acute radiation syndrome (H-ARS). It protects hematopoietic stem (HSC) and progenitor (HPC) cells and accelerates hematopoietic recovery by attenuating mitochondrial compromise, epigenetic downregulation of p53, and inhibition of histone acetylation at the promoters of genes involved in cell cycle, DNA repair and apoptosis. Since PGE2 mediates it effects through 4 conserved G-protein coupled receptors (EP1-4) we utilized highly selective EP receptor agonists to identify the EP receptors mediating radioprotection in H-ARS and evaluated the genes, cellular pathways and biological functions downstream of the EP receptors involved in HSC radioprotection. Radioprotection of mice from lethal radiation exposure was observed for the EP3 agonist sulprostone (65% survival) and the EP4 agonist rivenprost (50% survival), with the combination of EP3 + EP4 agonists providing 100% survival. Misoprostol, a PGE1 analog with similar EP receptor affinities as dmPGE2 also provided &gt;90% survival. The combination of EP3 and EP4 agonists was highly efficacious in accelerating recovery of all peripheral blood cell counts. Analysis of bone marrow HSPC populations from lethally irradiated mice by flow cytometry indicated that the EP3 + EP4 agonist combination trended closest to dmPGE2 in protecting total HSC and HPC, preventing early entry of these cells into cell cycle, and attenuating radiation-induced upregulation of the proapoptotic death receptor Fas, with similar activity also shown by misoprostol. Several genes involved in cell cycle and/or apoptosis control were upregulated (s1pr1, arrdc3, osm) or downregulated (hcar2 and cxcl10) in HSCs by all efficacious agonist treatments. Analysis of gene expression profiles and functional pathway analysis in HSC suggests that the EP4 receptor signals primarily through cAMP/PKA/CREB1, while EP3 signals primarily through a PI3K/Akt pathway initiated through activation of the Ras/Rho GTPases. In the combination setting, EP4 signaling appears dominant. Co-stimulation of EP3 and EP4 gave a stronger z-score for CREB1 activation with EP3 signaling augmenting/enhancing gene expression downstream of EP4 predominantly through CREB1. Comparison of KEGG pathways regulated by dmPGE2 and those regulated by the combination of EP3 + EP4 agonists indicate that both groups' TNF signaling pathways may be key functional components for radioprotection by dmPGE2 in HSC. Differentially expressed genes (DEG) associated with GTPase activity were observed in HSCs from mice treated with both EP3 and EP4 agonists likely contributing to their enhanced radioprotective effect mediated through the PI3K/Akt pathways downstream of both receptors. Some upstream regulators most strongly activated by dmPGE2 in bone marrow stromal cells overlapped with those observed in HSCs, with the most striking similarity being inhibition ","PeriodicalId":20903,"journal":{"name":"Radiation research","volume":" ","pages":"369-388"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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
A Murine Model of Radionuclide Lung Contamination for the Evaluation of Americium Decorporation Treatments. 放射性核素肺污染小鼠模型用于评价镅去除治疗的效果。
IF 2.5 3区 医学
Radiation research Pub Date : 2025-06-01 DOI: 10.1667/RADE-25-00001.1
Trevor Arino, Alexia G Cosby, Jennifer Alvarenga-Vasquez, Kirsten E Martin, Alex Rigby, Adrianna Reece-Newman, Shereen Aissi, Ethan Hallick, Isaac Jaro, Rebecca J Abergel
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